1. Literature Review Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

2. Targonwnik LE 1, Bolton JM 2, Metge CJ 3, Leung S 1, Sareen J 2,4. Selective Serotonin Reuptake Inhibitors Are Associated With a Modest Increase in the Risk of Upper Gastrointestinal Bleeding (UGIB). Am J Gastroenterol. 2009;104:1475-1482. 1 Section of Gastroenterology, Division of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; 2 Department of Psychiatry, University of Manitoba, Canada; 3 Department of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada; 4 Department of Community Health Sciences, Faculty of Medicine, Winnipeg, Manitoba, R3E3P4, Canada.

3. Introduction  Antidepressants are among the most extensively prescribed medications in the US.  The serotonin-specific reuptake inhibitors (SSRIs) are effective for the treatment of depression and general anxiety disorders.  Generally, SSRI’s are considered safer and exhibit a better side effect profile than previous generations of antidepressants.  For these reasons the SSRIs have become one of the most commonly prescribed class of antidepressants. MacGillivray S, et al. Br. Med Journal. 2003;326:1014-17. Gerretsen P, et al. Expert Opin Drug Metab Toxicol. 2008;4:1465-78. Jones CA, et al. Neuropharmacol. 2008;55:1056-65.

4. Introduction  Accumulation of case reports and meta-analysis have suggested and increased risk for UGI bleeding complications among chronic users of SSRIs.  SSRI’s inhibition of serotonin uptake in platelets is believed to impair the normal haemostatic mechanism, thereby predisposing chronic users of SSRI’s to UGI bleeding.  Factors that predispose to gastric and duodenal ulcers include: H. pylori, ASA, NSAID’s, smoking, alcohol, acid hypersecretion, age > 65 yrs, and COPD. Paton C, et al. Br M J. 2005;331:529-530. Turner MS, et al. J Intern Med.2007;261 :205-213. LiN, et al. Blood Coagul Fibrinol 1997;8:517-23. Malfertheiner P, et al. Lancet. 2009;374:1449-61.

5. Factors Influencing Platelet Activation & Adhesion Serotonin Epinephrine Collagen Platelet-Activating Factor Plasmin ADP Thrombin receptors PAR-4 & PAR-1 Thromboxane A2 Platelet Activation

6. Drugs Known to Inhibit Platelet Activation and Adhesion SSRI’s (via) Serotonin Clopidogrel (via) ADP Aspirin (via) Thromboxane A2 Platelet Inhibition

7. Aim The authors sought to determine: 1.The risk of adverse upper gastrointestinal outcomes with the use of SSRIs. 2.The combined risk of adverse upper gastrointestinal outcomes with SSRIs and NSAIDs. 3.Whether PPIs have a role in lowering risk of GI complications in susceptible individuals on SSRIs and NSAIDs. Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

8. Study Design: Methods Retrospective review of the Manitoba Population “Health Research Data Repository”  Cohort all Manitoba citizens > 18 yrs continuous enrollment in the health care plan  Study Time Interval April 1995 to March 2007  Cases included all admitted to hospital with diagnosis of UGI bleeding Included only UGIB admitted for > 24 hr Excluded variceal bleeding Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

9. Study Design: Methods Case Control Group (Each Subject Matched)  Admission date for non UGIB  Age + 3 yrs  Gender  Overall medical co-morbidity* (Johns Hopkins Adjusted Diagnostic Group score *Starfield B, et al. Health Serv Res.1991;26:53-74) Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

10. Study Design: Methods Determinants of Rx Exposure: SSRIs, NSAIDs, & PPIs  Calculation from Rx initial to next dispensed did not fall below 0.7 standard doses per day.  SSRI included list of Anatomical Therapeutic Chemical Classification System (ACT) Class N06B plus Venlafaxine – see table.  Exposure considered if medication used on or within 14-days of the date of hospital admission.  NSAID included non-selective NSAID or COX-2 inhibitors. Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

11. Anatomical Therapeutic Chemical Classification (ATC) Class NO6AB  N06AB Selective serotonin reuptake inhibitors N06AB02 Zimelidine N06AB03 Fluoxetine N06AB04 Citalopram N06AB05 Paroxetine N06AB06 Sertraline N06AB07 Alaproclate N06AB08 Fluvoxamine N06AB09 Etoperidone N06AB10 Escitalopram  Plus Serotonin-norepnephrine reuptake inhibitor N06AX16 Venlafaxine

12. Study Design: Methods Assessment of confounding variables  Comorbid Illness matched by ► Johns Hopkins Aggregate Diagnostic Group  Tracking Use of Other medications ► Warfarin ► Corticosteroids ► Clopidogrel ► H2-receptor antagonists ► Unable to track OTC aspirin use  History of GI disease ► Adjusted for GI care or EGD within 6 mo of index date Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

13. Study Design: Methods Statistics: Univariate analysis using χ² or Fisher exact test. Conditional multivariate logistic regression performed to identify independent variables. Regression analysis using SSRI as reference group to examine combined effects of PPIs and NSAIDs on SSRI users. Sub-analysis for sex, age, co-medications and co-morbidities. Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

14. Results:  910,346 subjects from Manitoba, Canada All > 18 yrs Manitoba Health Research Data Repository  1,552 subjects had UGIB  68,590 Matched Controls no UGIB Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

15. Characteristics of Subjects With UGIB vs. Matched Controls CharacteristicsCasesN=1,552ControlsN=68,590 P value Mean Age (yr) 68.969.8N/A % Male 57.656.4N/A SSRI alone 6218810.0016 NSAID alone 2635,266<0.001 PPI alone 602,681>0.2 SSRI + NSAID 23337<0.001 SSRI + PPI 63690.092 NASID + PPI 166220.108 SSRI + NSAID + PPI <5990.132 No SSRI/PPI/NSAID 111957335<0.001 SSRI < 28 days 0.70.40.028 SSRI 29-90 days 1.10.50.016 SSRI > 91 days 5.63.80.16 Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

16. Characteristics of Subjects With UGIB vs. Matched Controls CharacteristicsCasesN=1,552ControlsN=68,590 P value H2-receptor antagonist 1223224<0.001 Warfarin1402878<0.001 Clopidogrel671390<0.001 Corticosteroids521252<0.001 TCA’s1042830<0.001 CV Disease 49911514<0.001 Respiratory1384092<0.001 Renal disease 83735<0.001 Active malignancy 2076909<0.001 Depression38696<0.001 Schizophrenia6520.0018 UGI Diagnosis < 6mo 4979939<0.001 EGD < 6 mo 83724<0.001 Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

17. Results of Multi-Conditional Logistic Regression Analysis CharacteristicsMedicationsAdjustedOR 95% Confidence Interval No SSRI/NSAID/PPI 1 SSRI alone 1.431.09-1.89 NSAID alone 2.622.26-3.03 SSRI + NSAID 3.172.01-5.00 SSRI + PPI 0.560.24-1.30 NSAID + PPI 0.870.51-1.47 SSRI + NSAID + PPI 0.930.29-3.03 Warfarin1.701.39-2.07 Clopidogrel1.601.22-2.11 Corticosteroids1.110.80-1.53 TCA1.200.97-1.50 Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

18. Results of Multi-Conditional Logistic Regression Analysis CharacteristicsComorbiditiesAdjustedOR 95% Confidence Interval Cardiovascular1.861.62-2.13 Respiratory1.140.94-1.38 Hepatic9.476.25-14.33 Renal3.622.82-4.68 Active Malignancy 1.571.10-1.51 Alcohol Abuse 3.563.66-7.29 Depression1.571.07-2.28 Schizophrenia1.981.42-8.86 Acute hosp < 6 mo 2.101.70-2.30 Out Pt UGI Diagnosis 3.081.70-2.30 EGD < 6 mo 1.482.36-4.03 Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

19. Study Results:  SSRI use = 1.38 x ↑ risk for UGIB  SSRI use = 1.43 x ↑ risk for UGIB when adjusted for confounding variables  SSRI + NSAID = 3.17 x ↑ risk for UGIB  SSRI + NSAID ~ NSAID risk for UGIB  No ∆ in risk for UGIB by duration SSRI use  SSRI + PPI = >60% ↓ risk for UGIB Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

20. Duration of SSRI Use (Days) and Odds of UGIB 1.501.43 1.33 Adjusted Odds Ratio Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

21. Adjusted Odds Ratio for SSRIs & NSAIDs risk for UGIB and PPI Risk Reduction for UGIB ↓ 61% risk p = 0.036 ↓ 67% risk p = 0.001 ↓ 61% risk p = 0.056 Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

22. Study Conclusions  SSRI use is associated with a modest ↑ risk UGIB (1.38X).  The risk of UGIB is increased by co- morbid diseases and concomitant use of NSAIDs.  The risk for UGIB related to SSRI occurs within the first 30 days and risk is not increased further by prolonged use. Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

23. Study Summary  PPI Rx decreases SSRI UGIB risk  PPI + Any Study Rx Decreases risk for UGIB SSRI + PPI = ↓ 61% UGIB NSAID + PPI =↓ 67% UGIB SSRI + NSAID + PPI =↓ 61% UGIB Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

24. Study Summary  This retrospective nested Case control study clearly shows that SSRIs are associated with increase risk for UGIB.  The risk for UGIB from SSRI is equivalent to Warfarin and Clopidogrel, but less than NSAIDs alone.  The co-administration of PPI greatly decreases the risk for UGIB (>60%) for SSRI, NSAID and SSRI + NSAID.  Co-morbid factors that accentuate SSRI UGIB risk include: Hepatic disease Renal disease Alcohol abuse Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

25. Reviewer Comments Targonwnik, et al, fail answer the following questions? Should selected patients on chronic SSRIs receive co-administration of a PPI to prevent UGIB? Should patients on SSRI plus other drugs (ASA, NSAIDs, Warfarin, & Clopidogrel) known to increase risk of UGIB be considered for prophylactic PPI? Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

26. Reviewer Comments 3.Should all patients needing SSRI, be evaluated for infection with H. pylori as is a treatable and modifiable risk factor for ulcer and UGIB? 4.Should patients needing SSRI, be screened for co-morbidities (Hepatic > Alcoholism > Renal > Schizophrenia > UGI Disease > Cardiovascular disease) also linked to UGIB risk? Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.

27. Reviewer Conclusions 1.The clinician is urged to remember that SSRIs are used with increasing frequency among the elderly for depression. This select group of the population is already at ↑ risk of PUD:  Other Rx: ASA, NSAID’s, Clopidogrel, & Warfarin  Co-morbid illness: Hepatic, Renal, Cardiovasc & alcoholism  H. pylori infection 2.We should be mindful of these cumulative risks and offer our elderly patients on SSRIs counter measures to avert UGIB, i.e., treatment of H pylori, avoid ulcerogenic Rx, & PPI prophylaxis for those at high risk. Targonwnik LE, et al. Am J Gastroenterol. 104;1475-1482.