bmj open · for peer review only 1 use of non-steroidal anti-inflammatory drugs and proton pump...

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

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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1

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

selective inhibitor users: a nationwide register-based study. Clin Drug Investig.

2008;28(11):687-695.

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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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.


(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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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.


(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


BMJ Open on D

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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



1,3, Claes Söderlund, 9


1, 4 10

11

Affiliations: 12

1 Upper Gastrointestinal Research, Department of Molecular Medicine and Surgery, 13


14

2 Section of Upper Gastrointestinal Surgery, Department of Surgery, Stockholm South 15


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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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

1. Blatchford O, Davidson LA, Murray WR, et al. Acute upper gastrointestinal haemorrhage in 16

west of Scotland: case ascertainment study. BMJ. Aug 30 1997;315(7107):510-514. 17

2. van Leerdam ME, Vreeburg EM, Rauws EA, et al. Acute upper GI bleeding: did anything 18

change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 19

1993/1994 and 2000. Am J Gastroenterol. Jul 2003;98(7):1494-1499. 20

3. Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: 21

a population-based study. Am J Gastroenterol. Feb 1995;90(2):206-210. 22

4. Yavorski RT, Wong RK, Maydonovitch C, et al. Analysis of 3,294 cases of upper 23

gastrointestinal bleeding in military medical facilities. Am J Gastroenterol. Apr 24

1995;90(4):568-573. 25

5. Vreeburg EM, Snel P, de Bruijne JW, et al. Acute upper gastrointestinal bleeding in the 26

Amsterdam area: incidence, diagnosis, and clinical outcome. Am J Gastroenterol. Feb 27

1997;92(2):236-243. 28

6. Hearnshaw SA, Logan RF, Lowe D, et al. Acute upper gastrointestinal bleeding in the UK: 29

patient characteristics, diagnoses and outcomes in the 2007 UK audit. Gut. Oct 30

2011;60(10):1327-1335. 31

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7. Paspatis GA, Matrella E, Kapsoritakis A, et al. An epidemiological study of acute upper 1

gastrointestinal bleeding in Crete, Greece. Eur J Gastroenterol Hepatol. Nov 2

2000;12(11):1215-1220. 3

8. Barkun A, Sabbah S, Enns R, et al. The Canadian Registry on Nonvariceal Upper 4

Gastrointestinal Bleeding and Endoscopy (RUGBE): Endoscopic hemostasis and proton pump 5

inhibition are associated with improved outcomes in a real-life setting. Am J Gastroenterol. 6

Jul 2004;99(7):1238-1246. 7

9. Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta-analysis of proton pump 8

inhibitor therapy in peptic ulcer bleeding. BMJ. Mar 12 2005;330(7491):568. 9

10. Wettermark B, Hammar N, Fored CM, et al. The new Swedish Prescribed Drug Register--10

opportunities for pharmacoepidemiological research and experience from the first six 11

months. Pharmacoepidemiol Drug Saf. Jul 2007;16(7):726-735. 12

11. Hermansson M, Ekedahl A, Ranstam J, et al. Decreasing incidence of peptic ulcer 13

complications after the introduction of the proton pump inhibitors, a study of the Swedish 14

population from 1974-2002. BMC Gastroenterol. 2009;9:25. 15

12. Leontiadis GI, Sharma VK, Howden CW. WITHDRAWN: Proton pump inhibitor treatment for 16

acute peptic ulcer bleeding. Cochrane Database Syst Rev.5:CD002094. 17

13. Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and 18

proton-pump inhibitors: a cohort study. Ann Intern Med. Mar 16;152(6):337-345. 19

14. Zed PJ, Loewen PS, Slavik RS, et al. Meta-analysis of proton pump inhibitors in treatment of 20

bleeding peptic ulcers. Ann Pharmacother. Dec 2001;35(12):1528-1534. 21

15. Di Fiore F, Lecleire S, Merle V, et al. Changes in characteristics and outcome of acute upper 22

gastrointestinal haemorrhage: a comparison of epidemiology and practices between 1996 23

and 2000 in a multicentre French study. Eur J Gastroenterol Hepatol. Jun 2005;17(6):641-647. 24

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, et al. Appropriateness of treatment recommendations for 33

PPI in hospital discharge letters. European journal of clinical pharmacology. Dec 34

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

38

39

40

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44

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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


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


(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


25


(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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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



1,3, Claes Söderlund, 9


1, 4 10

11

Affiliations: 12

1 Upper Gastrointestinal Research, Department of Molecular Medicine and Surgery, 13


14

2 Section of Upper Gastrointestinal Surgery, Department of Surgery, Stockholm South 15


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


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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5

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

1. Blatchford O, Davidson LA, Murray WR, Blatchford M, Pell J. Acute upper gastrointestinal 16

haemorrhage in west of Scotland: case ascertainment study. BMJ. Aug 30 17

1997;315(7107):510-514. 18

2. van Leerdam ME, Vreeburg EM, Rauws EA, et al. Acute upper GI bleeding: did anything 19

change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 20

1993/1994 and 2000. Am J Gastroenterol. Jul 2003;98(7):1494-1499. 21

3. Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: 22

a population-based study. Am J Gastroenterol. Feb 1995;90(2):206-210. 23

4. Yavorski RT, Wong RK, Maydonovitch C, Battin LS, Furnia A, Amundson DE. Analysis of 3,294 24

cases of upper gastrointestinal bleeding in military medical facilities. Am J Gastroenterol. Apr 25

1995;90(4):568-573. 26

5. Vreeburg EM, Snel P, de Bruijne JW, Bartelsman JF, Rauws EA, Tytgat GN. Acute upper 27

gastrointestinal bleeding in the Amsterdam area: incidence, diagnosis, and clinical outcome. 28

Am J Gastroenterol. Feb 1997;92(2):236-243. 29

6. Hearnshaw SA, Logan RF, Lowe D, Travis SP, Murphy MF, Palmer KR. Acute upper 30

gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 31

2007 UK audit. Gut. Oct 2011;60(10):1327-1335. 32

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7. Paspatis GA, Matrella E, Kapsoritakis A, et al. An epidemiological study of acute upper 1

gastrointestinal bleeding in Crete, Greece. Eur J Gastroenterol Hepatol. Nov 2

2000;12(11):1215-1220. 3

8. Barkun A, Sabbah S, Enns R, et al. The Canadian Registry on Nonvariceal Upper 4

Gastrointestinal Bleeding and Endoscopy (RUGBE): Endoscopic hemostasis and proton pump 5

inhibition are associated with improved outcomes in a real-life setting. Am J Gastroenterol. 6

Jul 2004;99(7):1238-1246. 7

9. Leontiadis GI, Sharma VK, Howden CW. Systematic review and meta-analysis of proton pump 8

inhibitor therapy in peptic ulcer bleeding. BMJ. Mar 12 2005;330(7491):568. 9

10. Wettermark B, Hammar N, Fored CM, et al. The new Swedish Prescribed Drug Register--10

opportunities for pharmacoepidemiological research and experience from the first six 11

months. Pharmacoepidemiol Drug Saf. Jul 2007;16(7):726-735. 12

11. Hermansson M, Ekedahl A, Ranstam J, Zilling T. Decreasing incidence of peptic ulcer 13

complications after the introduction of the proton pump inhibitors, a study of the Swedish 14

population from 1974-2002. BMC Gastroenterol. 2009;9:25. 15

12. Leontiadis GI, Sharma VK, Howden CW. WITHDRAWN: Proton pump inhibitor treatment for 16

acute peptic ulcer bleeding. Cochrane Database Syst Rev.5:CD002094. 17

13. Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and 18

proton-pump inhibitors: a cohort study. Ann Intern Med. Mar 16;152(6):337-345. 19

14. Zed PJ, Loewen PS, Slavik RS, Marra CA. Meta-analysis of proton pump inhibitors in 20

treatment of bleeding peptic ulcers. Ann Pharmacother. Dec 2001;35(12):1528-1534. 21

15. Di Fiore F, Lecleire S, Merle V, et al. Changes in characteristics and outcome of acute upper 22

gastrointestinal haemorrhage: a comparison of epidemiology and practices between 1996 23

and 2000 in a multicentre French study. Eur J Gastroenterol Hepatol. Jun 2005;17(6):641-647. 24

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


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


(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


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


6

7


(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


7

8

9


(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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