Contents Appendix 1A: List of Exposure Drugs in Nsaids and Pneumonia Analysis

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Contents Appendix 1a: List of exposure drugs in NSAIDs and Pneumonia analysis ...... 2 Appendix 1b: List of comparator drugs in NSAIDs and Pneumonia analysis ...... 3 Appendix 2: List of ICD-9 codes used to define upper respiratory disease for subgroup analysis in NSAIDs and pneumonia example ...... 4 Appendix 3: Association between non-selective NSAIDs and GI bleed ...... 5

Appendix 1a: List of exposure drugs in NSAIDs and Pneumonia analysis

Butylpyrazolidines Acetic acid Oxicams Propionic acid Fenamates Coxibs Other derivatives and derivatives** related Phenylbutazone indometacin piroxicam ibuprofen mefenamic acid celecoxib nabumetone Mofebutazone sulindac tenoxicam naproxen tolfenamic acid rofecoxib niflumic acid Oxyphenbutazone tolmetin droxicam ketoprofen flufenamic acid valdecoxib azapropazone Clofezone meclofenamic zomepirac lornoxicam fenoprofen acid parecoxib glucosamine Kebuzone diclofenac meloxicam fenbufen etoricoxib benzydamine meloxicam, glucosaminoglycan alclofenac combinations benoxaprofen lumiracoxib polysulfate bumadizone suprofen polmacoxib proquazone etodolac pirprofen orgotein lonazolac flurbiprofen nimesulide fentiazac indoprofen feprazone acemetacin tiaprofenic acid diacerein difenpiramide oxaprozin morniflumate oxametacin ibuproxam tenidap proglumetacin dexibuprofen oxaceprol ketorolac flunoxaprofen chondroitin sulfate aceclofenac alminoprofen feprazone, combinations bufexamac dexketoprofen nabumetone indometacin, combinations naproxcinod niflumic acid diclofenac, ibuprofen, combinations combinations ketoprofen, combinations naproxen and misoprostol All included drugs oral route of administration. **Exclude PPI combinations Appendix 1b: List of comparator drugs in NSAIDs and Pneumonia analysis

 Diclofenac Sodium (topical route of administration). Appendix 2: List of ICD-9 codes used to define upper respiratory disease for subgroup analysis in NSAIDs and pneumonia example

ICD-9 Code Description 460 ACUTE NASOPHARYNGITIS (COMMON COLD) 462 ACUTE PHARYNGITIS 463 ACUTE TONSILLITIS 461.0 ACUTE MAXILLARY SINUSITIS 461.1 ACUTE FRONTAL SINUSITIS 461.2 ACUTE ETHMOIDAL SINUSITIS 461.3 ACUTE SPHENOIDAL SINUSITIS 461.8 OTHER ACUTE SINUSITIS 461.9 ACUTE SINUSITIS UNSPECIFIED 464.0 ACUTE LARYNGITIS 464.0 ACUTE LARYNGITIS WITHOUT OBSTRUCTION 464.0 ACUTE LARYNGITIS WITH OBSTRUCTION 464.1 ACUTE TRACHEITIS 464.1 ACUTE TRACHEITIS WITHOUT OBSTRUCTION 464.1 ACUTE TRACHEITIS WITH OBSTRUCTION 464.2 ACUTE LARYNGOTRACHEITIS 464.2 ACUTE LARYNGOTRACHEITIS WITHOUT OBSTRUCTION 464.2 ACUTE LARYNGOTRACHEITIS WITH OBSTRUCTION 464.3 ACUTE EPIGLOTTITIS 464.3 ACUTE EPIGLOTTITIS WITHOUT OBSTRUCTION 464.3 ACUTE EPIGLOTTITIS WITH OBSTRUCTION 464.4 CROUP 464.5 SUPRAGLOTTITIS UNSPECIFIED 464.5 SUPRAGLOTTITIS UNSPECIFIED WITHOUT OBSTRUCTION 464.5 SUPRAGLOTTITIS UNSPECIFIED WITH OBSTRUCTION 465.0 ACUTE LARYNGOPHARYNGITIS 465.8 ACUTE UPPER RESPIRATORY INFECTIONS OF OTHER MULTIPLE SITES 465.9 ACUTE UPPER RESPIRATORY INFECTIONS OF UNSPECIFIED SITE

Appendix 3: Association between non-selective NSAIDs and GI bleed

Exposure: Non-selective NSAIDs; defined using WHO ATC codes M01AB (acetic acid derivatives and related substances), M01AC (oxicams), M01AE (propionic derivatives), M01AG (Fenamates)

Comparator: Celecoxib

Exclusions: history of GI bleed, no continuous (365 days) medical or pharmacy enrollment prior to cohort entry, exposure to exposure/comparator drug in previous 365 days, exposure to both exposure and comparator on cohort entry date.

Outcome: GI bleed defined using the following ICD-9 codes: 456.0x, 530.70, 531.xx, 532.xx, 533.xx, 534.xx, 535.01-535.51, 535.61, 537.83, 578.xx (Cooper et al, Gastrointest Endosc, 2000).

Definition modified to remove: 531.3, 531.7, 531.9, 532.3, 532.7, 532.9, 533.3, 533.7, 533.9, 534.3, 534.7 and 534.9 as they specify “without hemorrhage”

Covariates:

 Age and gender  Chronic renal insufficiency, Diabetes, Hypertension, Osteoarthritis, Rheumatoid arthritis, MI, stable Angina, unstable angina, cancer  Anti-platelet drugs, warfarin, oral steroids, insulin, statins, proton pump inhibitors, h2 antagonists, anti-hypertensive drugs, opioids  Number of inpatient visits in 365 days prior to cohort entry, number of outpatient visits in 365 days prior to cohort entry, unique number of drugs in 365 days prior to cohort entry, combined comorbidity index in 365 days prior to cohort entry

Approach to deal with confounding: Matching 1:1 on propensity score, within 1% of propensity score.

Analysis: Cox proportional hazards. Follow up ended on earliest of; end of exposure, switch/addition of comparator/exposure, 365 days follow up, end of medical/pharmacy enrollment, death, end of study period (30th September 2015).

Subgroups: Aged < / ≥ 60 years.

Results:

Figure 1: Flowchart for cohort entry

Table 1: Baseline characteristics for new initiators of ns-NSAIDs (exposure) and new initiators of celecoxib (comparator)

Table 2: Hazard ratios and 95% CI for main analysis and subgroup analysis

Number of people available for analysis in MarketScan Data N= 185,306,593

Users of exposure/comparator from July 1 2012-Jun 30 2015 N= 10,157,232 Excluded:

Insufficient medical enrollment (<365 days pre-index) n = 2,456,678 Insufficient pharmacy enrollment (<365 days pre-index) n= 90,672 Prior use of exposure (within 365 days pre-index) n = 1,561,406 Prior use of referent (within 365 days pre-index) n = 184,083 Use of both agents on index date n= 436 New users remaining n= 5,863,957 Excluded:

History of GI bleed prior to index date n= 175,917 Final Cohort N= 5,688,040

Figure 1: Flowchart describing study cohort inclusion for the GI bleed example

Table 1: Baseline Characteristics for new initiators of ns-NSAIDs (Exposure) and new initiators of celecoxib (comparator)

Unmatched Matched Celecoxib ns-NSAIDs Difference (%) Celecoxib ns-NSAIDs Difference n= 150,545 n=5,537,495 n= 150,245 n=150,245 (%) Mean Age x x x x x X Female n (%) 88,841 (59.0) 3,248,362 (58.7) 0.4 88,655 (59.0) 89,319 (59.4) -0.4 Comorbidities n (%) Previous MI 4,800 (3.2) 71,168 (1.3) 1.9 4,790 (3.2) 4,569 (3.0) 0.1 Stable Angina 7,548 (5.0) 117,627 (2.1) 2.9 7,533 (5.0) 7,274 (4.8) 0.2 Unstable Angina 4,446 (3.0) 68,922 (1.2) 1.7 4,429 (2.9) 4,274 (2.8) 0.1 Hypertension 84,715 (56.3) 1,784,580 (32.2) 24.0 84,566 (56.3) 84,604 (56.3) -0.0 Heart Failure 7,516 (5.0) 94,981 (1.7) 3.3 7,502 (5.0) 7,045 (4.7) 0.3 Diabetes 31,945 (21.2) 687,851 (12.4) 8.8 31,879 (21.2) 31,625 (21.0) 0.2 Chronic renal insufficiency 5,769 (3.8) 93,300 (1.7) 2.1 5,763 (3.8) 5,410 (3.6) 0.2 Cancer 79,529 (52.8) 1,847,774 (33.4) 19.5 79,397 (52.8) 80,258 (53.4) -0.6 Osteoarthritis 73,729 (49.0) 878,599 (15.9) 33.1 73,605 (49.0) 74,529 (49.6) -0.6 Rheumatoid arthritis 7,667 (5.1) 83,098 (1.5) 3.6 7,656 (5.1) 7,160 (4.8) 0.3 Drugs Anti-platelets 9,196 (6.1) 117,950 (2.1) 4 9,181 (6.1) 8,744 (5.8) 0.3 Warfarin 12,308 (8.2) 88,212 (1.6) 6.6 12,286 (8.2) 10,391 (6.9) 1.3 Oral steroids 74,584 (49.5) 2,024,465 (36.6) 13.0 74,435 (49.5) 75,979 (50.6) -1.0 PPIs 57,878 (38.4) 1,107,869 (20.0) 18.4 57,790 (38.5) 58,497 (38.9) -0.5 H2 antagonists 12,281 (8.2) 307,387 (5.6) 2.6 12,253 (8.2) 11,886 (7.9) 0.2 Anti-hypertensives 83,906 (55.7) 1,809,503 (32.7) 23.1 83,769 (55.8) 84,058 (55.9) -0.2 Statins 60,492 (40.2) 1,128,025 (20.4) 19.8 60,400 (40.2) 60,651 (40.4) -0.2 Insulin 5,438 (3.6) 131,193 (2.4) 1.2 5,426 (3.6) 5,303 (3.5) 0.1 Opioids 56,745 (37.7) 1,086,476 (19.6) 18.1 56,637 (37.7) 56,706 (37.7) -0.0

Combined comorbidity index 0.37 (1.41) 0.15 (0.92) 0.22 0.37 (1.41) 0.33 (1.38) 0.04 Health Service Utilization mean (sd) Number of unique inpatient 0.19 (0.53) 0.11 (0.39) 0.08 0.19 (0.53) 0.16 (0.54) 0.03 events Number of unique drugs 8.19 (5.94) 5.13 (4.78) 3.06 8.19 (5.94) 8.17 (6.06) 0.02 Number of unique outpatient 18.15 (17.66) 10.65 (12.56) 7.50 18.16 (17.66) 17.78 (18.54) 0.38 visits

Table 2: Hazard ratios and 95% CI for main analysis and subgroup analyses

n outcomes Hazard Ratio 95% CI Main 300,490 980 1.13 0.99 – 1.28 < 60 years 166528 361 1.10 0.89 – 1.36 ≥60 years 133958 646 1.27 1.09 – 1.49 Hazard ratios from 1:1 propensity score matched cohorts.

Interpretation of results: The large-scale sequence symmetry analysis found an association between NSAIDs and anti-ulcer drugs (SR 1.71, 95% CI 1.67 – 1.74). NSAIDs were extracted on the basis of ATC codes M01A which is a mixture of selective and non-selective NSAIDs. Thus, the signal was likely a mixture of true bleeding from non-selective NSAIDs and bleeding associated with coxibs that occurred due to confounding by indication. To disentangle this mixing of effects, and knowing what the true answer in this analysis should be (i.e. non-selective NSAIDs are associated with bleeding) we separated selective and non-selective NSAIDs into the exposure and comparator groups. We extracted data on multiple confounding variables, and carried out propensity score matching. In this way, we attempted to reduce confounding by indication. Our results demonstrate a trend towards increased risk of bleeding associated with exposure to non-selective NSAIDs (HR 1.13, 95% CI 0.99 – 1.28). The results become stronger when restricted to a population aged >= 60years (HR, 1.27, 95% CI 1.09 – 1.49), and agree with previous estimates in the literature (Patterson, 2008).