CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2006;4:1337–1345
`
`Impact of Adherence to Concomitant Gastroprotective Therapy
`on Nonsteroidal-Related Gastroduodenal Ulcer Complications
`
`JAY L. GOLDSTEIN,* KIMBERLY B. HOWARD,‡ SURREY M. WALTON,* TRENT P. MCLAUGHLIN,§
`AND DENISE T. KRUZIKAS¶
`*University of Illinois at Chicago, Chicago, Illinois; ‡Pfizer Inc, New York, New York; §NDCHealth, Phoenix, Arizona; and ¶NDCHealth, Yardley, Pennsylvania
`
`Background & Aims: The clinical impact of nonadherence
`to gastroprotective agents (GPAs) coprescribed with anti-
`inflammatory therapies has not been evaluated. In a large,
`commercial, managed-care database, we retrospectively charac-
`terized the use of GPAs among patients receiving nonselective
`nonsteroidal anti-inflammatory drugs (ns-NSAIDs) or cyclooxy-
`genase-2–selective inhibitors (coxibs) and determined the im-
`pact of nonadherence on the likelihood of gastroduodenal ulcer
`complications. Methods: Analyses identified the populations
`of patients with concomitant histamine-2 receptor antagonist
`or proton pump inhibitor (PPI) therapy and determined adher-
`ence with the prescribed therapy with respect to the duration of
`anti-inflammatory treatment. Multivariate regression analyses
`modeled the association between adherence with concomitant
`protective therapy and the likelihood of upper gastrointestinal
`(GI) complications including peptic ulcer disease, ulcer, and/or
`upper-GI bleed. Results: Among 144,203 patients newly pre-
`scribed anti-inflammatory therapies, 1.8% received concomitant
`GPA treatment (ns-NSAIDs, 1.4% vs coxibs, 2.6%; P ⬍ .0001).
`The likelihood of GPA use increased with the presence of risk
`factors: age older than 65 years (odds ratio [OR], 1.40; 95%
`confidence interval [CI], 1.3–1.5) and prior history of peptic
`ulcer disease (OR, 2.5; 95% CI, 1.8 –3.3), esophagitis/gastro-
`esophageal reflux (OR, 3.8; 95% CI, 3.5– 4.1), ulcer/upper-GI
`bleed (OR, 1.4; 95% CI, 1.2–1.5), or gastritis (OR, 2.5; 95% CI,
`2.2–2.8). Of patients receiving concomitant PPI therapy, 68%
`had adherence rates of 80% or more. A significantly higher risk
`of upper-GI ulcers/complications was observed in ns-NSAID
`patients with adherence rates of less than 80% compared with
`adherence rates of 80% or more (OR, 2.4; 95% CI, 1.0 –5.6), but
`no such relationship was observed among patients who took
`coxibs. Conclusions: Few patients receive concomitant GPA
`therapy when prescribed anti-inflammatory treatment, al-
`though use increased with the presence of risk factors. Adher-
`ence to concomitant therapy is paramount to reducing GI
`events among ns-NSAID users and educational efforts should
`be undertaken to promote use of and adherence to GPA therapy
`among these patients.
`
`The management of arthritis and chronic pain syndromes
`
`often involves continued use of analgesic medications.1,2
`Because of their efficacy and relatively inexpensive cost, nonse-
`lective nonsteroidal anti-inflammatory drugs (ns-NSAIDs) con-
`tinue to be the mainstay of arthritis and pain management
`despite their associated risk of gastrointestinal (GI) toxicity.3– 6
`With the aim of circumventing the upper-GI toxicity associated
`
`with use of ns-NSAIDs, multiple studies have shown that co-
`administration of so-called gastroprotective agents (GPAs) such as
`misoprostol or proton pump inhibitors (PPIs), reduces the rate
`of endoscopic gastric and/or duodenal ulcers compared with
`ns-NSAIDs alone.7–10 In the case of misoprostol, there is also
`evidence of a reduction in the rate of upper-GI complications.11
`Although a single prospective endoscopic clinical trial sug-
`gested high-dose famotidine (40 mg twice a day) reduces the
`rate of endoscopic gastroduodenal ulcers compared with
`ns-NSAIDs alone,12 there is a paucity of evidence that hista-
`mine-2 receptor antagonists (H2RAs) are effective in reducing
`ns-NSAID–related upper-GI ulcer complications.3,13,14
`As an alternative to the use of coprescribed GPAs, cyclooxy-
`genase-2–selective inhibitors (coxibs) are less likely to be asso-
`ciated with the development of endoscopic gastric and duode-
`nal ulcers and upper-GI complications.15–19 Recent studies also
`have suggested that PPIs co-administered with ns-NSAIDs are
`comparable with coxibs with respect to the rate of recurrent
`upper-GI ulcer bleeding in high-risk patients.20 –22
`Based on these data, clinical guidelines have been forwarded
`by expert panels and developed by several national professional
`societies addressing the appropriate use of preventive strategies
`for patients at high risk. These guidelines generally recommend
`the concomitant use of GPAs such as a PPI or misoprostol, or
`the use of a coxib alone in place of an ns-NSAID among
`patients at high risk for GI complications.2,23–27 Well-recog-
`nized risk factors for upper-GI ulcer complications include
`advanced age, history of upper-GI ulcers or bleeding, and con-
`comitant use of corticosteroids or anticoagulants.3,11,28 –33
`Despite the available data and the integrated guidelines,
`evidence suggests that significant proportions of high-risk pa-
`tients are not receiving any protective strategies and, of those
`who do receive GPAs, many are treated inadequately with inef-
`fective therapies.34,35 For example, and despite the wealth of
`evidence supporting greater efficacy of PPIs compared with
`H2RAs, it is unfortunately still relatively common for physicians
`in clinical practice to prescribe standard doses of H2RAs (eg,
`ranitidine 150 mg twice a day) for prevention of ns-NSAID–
`induced GI adverse events.35 The fact that various national
`
`Abbreviations used in this paper: CI, confidence interval; GERD,
`gastroesophageal reflux disorder; GI, gastrointestinal; GPA, gastropro-
`tective agents; H2RA, histamine-2 receptor antagonist; ICD-9-CM, In-
`ternational Classification of Diseases, Ninth Revision, Clinical Modifi-
`cation; ns-NSAID, nonselective nonsteroidal anti-inflammatory drug;
`OR, odds ratio; PPI, proton pump inhibitor; PUD, peptic ulcer disease.
`© 2006 by the AGA Institute
`1542-3565/06/$32.00
`doi:10.1016/j.cgh.2006.08.016
`
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`1338 GOLDSTEIN ET AL
`
`CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 11
`
`preventive guidelines for patients at high risk for NSAID-asso-
`ciated upper-GI toxicity are not applied uniformly in the clin-
`ical setting has been highlighted and quantified further. In a
`recent evaluation by Abraham et al27 based on the use of a
`national Department of Veterans Affairs database, less than
`30% of veterans considered to be at high risk for NSAID-
`associated upper-GI toxicity were found to receive appropriate
`therapies.
`Patient adherence remains one of the important challenges
`of day-to-day clinical practice, and even when at-risk patients
`are identified and prescribed appropriate preventive strategies,
`nonadherence to the use of these medications may impact
`greatly on both short-term and long-term clinical out-
`comes.36 –38 Specific to anti-inflammatory treatment, Sturken-
`boom et al35 determined that only 37% of patients newly re-
`ceiving ns-NSAIDs had a greater than 75% adherence to their
`concomitant GPA therapy regimen. However, this study did not
`evaluate the clinical impact of this high level of nonadherence
`and, as such, leaves the issue of long-term GI safety and effec-
`tiveness of coprescription open to question. Therefore, this
`retrospective database study was undertaken to characterize the
`use of GPAs among patients receiving coxibs or ns-NSAIDs and
`to determine the impact of adherence to concomitant GPA
`therapy on the likelihood of coxib- and ns-NSAID–related gas-
`troduodenal toxicity.
`
`Patients and Methods
`This retrospective study was based on the patient-level
`clinical, longitudinal PharMetrics Integrated Outcomes data-
`base (PharMetrics, Watertown, MA), which offers administra-
`tive claims information collected from approximately 75 com-
`mercial managed-care plans covering more than 43 million
`enrollees across the United States. The database includes inpa-
`tient and outpatient diagnoses, procedures, and prescriptions
`filled within the plans. All medical and pharmaceutical claims
`include dates of service, and prescription data include date
`filled/administered, days supplied, and quantity dispensed. Ad-
`ditional data elements include demographic variables (age, sex,
`geographic region), health plan type (eg, health maintenance
`organization, preferred provider organization), payer type (eg,
`commercial, self-pay), provider specialty, and start and stop
`dates for plan enrollment. For the purposes of this study, we
`accessed a subset of 35 commercial managed-care plans from
`the PharMetrics database in which access to coxibs and GPA
`therapies were known to be available. We restricted our analysis
`to commercial managed-care plans in which claims for the
`agents of interest were recorded during the time frame of this
`study as an indicator showing the ability of physicians to
`prescribe these medications.
`
`Patient Sample
`The study time frame spanned a 3-year period from
`January 1, 2000, to December 31, 2002. Patients were eligible for
`inclusion in the study if they had an index prescription claim
`for an ns-NSAID or coxib and at least 1 refill for the same
`medication during this time frame. Because this study intended
`to examine the effects of long-term therapy, patients were
`excluded if they had less than a 10-day supply for their index
`medication or gaps in therapy of 120 days or more. Inclusion
`criteria also required no prescription claims for ns-NSAIDs,
`
`coxibs, or GPAs (misoprostol, PPIs, or H2RAs) during the 12
`months before the index prescription date and 12 continuous
`months of enrollment in the plan both before and after the
`index prescription date. Patient data were analyzed during the
`12-month preperiod to determine baseline demographic char-
`acteristics and the patients were followed-up for up to 12
`months after the index prescription date to evaluate subsequent
`upper-GI outcomes related to ns-NSAID or coxib therapy.
`Treatment cohorts were defined by the index prescription
`claim during the study period. Ns-NSAIDs included ibuprofen,
`naproxen, nabumetone, diclofenac sodium, diclofenac potas-
`sium, etodolac, piroxicam, oxaprozen, sulindac, meloxicam, ke-
`toprofen, flurbiprofen, and fenoprofen calcium. In these plans,
`aspirin use could not be measured objectively. Coxib products
`included celecoxib, rofecoxib, and valdecoxib. Patients were
`permitted to switch medications within their index cohort. For
`example, if a patient was initiated on celecoxib and had a
`subsequent prescription for a different coxib drug, they re-
`mained a coxib patient and were retained in the study. Simi-
`larly, a patient with an index claim for ibuprofen who switched
`to a different ns-NSAID treatment still was considered an
`ns-NSAID patient in the analyses. However, switching between
`treatment cohorts was not permitted; patients with any subse-
`quent claims within 12 months after their index date for a
`medication listed in the alternative treatment group (ie, a coxib
`patient who had a subsequent claim for an ns-NSAID, or vice
`versa) were excluded from the analyses. In the case of patients
`switching between cohorts, the index time to the switch was not
`included in the analyses.
`Demographic data were collected to describe treatment co-
`horts with respect to age, sex, and health status. Health status
`was determined by comorbid illness, measured by the most
`common 3-digit International Classification of Diseases, Ninth
`Revision, Clinical Modification (ICD-9-CM) codes recorded in
`secondary diagnosis positions on prior medical claims. Two
`standard measurement tools were used to evaluate patient
`health status further, the Charlson Comorbidity Index and the
`Chronic Disease Score.39,40 In addition, analyses assessed the
`frequency of coded GI diagnoses during the 12 months before
`the index prescription. Diagnoses considered for this analysis
`included peptic ulcer disease (PUD), esophagitis/gastroesopha-
`geal reflux disease, ulcer/upper-GI bleed, and gastritis. These
`diagnoses were identified through medical claims containing
`the following ICD-9-CM codes: 533.xx (PUD); 530.xx (esoph-
`agitis/gastroesophageal reflux disease); 531.xx, 532.xx, 534.xx,
`and 578.xx (ulcer/upper-GI bleed); and 535.xx (gastritis).
`Based on the available data, patients were grouped into 4
`cohorts based on their use of ns-NSAIDs or coxibs with or
`without concomitant use of GPAs. Prescription claims were
`used to determine concomitant acid-suppressive GPA ther-
`apy, defined as initiation of PPI or H2RA use up to 14 days
`after the ns-NSAID/coxib index prescription. In this analysis,
`H2RAs were included in the GPA treatment definition be-
`cause we assumed that it was a cognitive action taken by
`prescribers with the presumable intention of preventing sub-
`sequent GI events.
`Analyses also determined the number and percentage of
`patients with GI diagnoses within 12 months before the index
`prescription date. Within the ns-NSAID and coxib cohorts, ␹2
`analyses compared the proportion of concomitant and noncon-
`comitant patients with prior GI diagnoses.
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`Likelihood of Initiating Concomitant
`Gastroprotective Therapy
`The ␹2 analyses first compared the proportion of con-
`comitant PPI/H2RA patients between ns-NSAID and coxib co-
`horts. Logistic regression analyses then modeled the likelihood
`of initiating concomitant therapy, with the index medication as
`the primary independent variable of interest and specific risk
`factors as predictors of secondary interest.11,31,41 Three risk
`factors were of particular interest to this study because of their
`association with increased risk of GI events: patient age older
`than 65 years, previous ulcer diagnosis, and anticoagulant and/or
`steroid use. Results were adjusted for patient age and sex.
`
`Impact of Adherence on Patient Outcomes
`The effectiveness of adherence with concomitant GPA
`therapy on subsequent upper-GI complications was evaluated.
`These analyses only included PPIs as the appropriate GPA
`therapy because they are believed to be effective in reducing the
`incidence of upper-GI ulcers and complications compared with
`H2RAs.8,12,20,42,43
`Adherence to concomitant therapy was determined using a
`ratio of dispensed days’ supply of PPI and ns-NSAIDs or coxibs.
`The duration of follow-up evaluation could extend for up to 12
`months after the index ns-NSAID/coxib prescription date,
`given that there were no treatment gaps of greater than 120
`days. Adherence rates were calculated by normalizing the total
`days’ supply of PPI therapy by the total days’ supply of ns-
`NSAID/coxib therapy as follows:
`
`Adherence 共%兲
`
`⫽冉
`
`兺 Dispensed PPI days’ supply
`兺 Dispensed anti-inflammatory drug days’ supply
`
`冊 ⫻ 100
`
`Adherence was capped at 100% because the intent was to
`identify PPI coverage over the course of ns-NSAID/coxib treat-
`ment. It was considered a continuous variable ranging from 0%
`to 100% and also as a categoric variable with 5 levels of adher-
`ence: 0%–20% to 80%–100%.
`A priori, the study hypothesized that the likelihood of ad-
`herence to concomitant GPA therapy decreases as the days’
`supply of anti-inflammatory treatment increases. Because ad-
`herence might change over the duration of anti-inflammatory
`treatment with the possibility that patients on therapy for
`longer durations might have increased rates of nonadherence
`with time, we evaluated the proportion of patients with PPI
`adherence of 80% or greater according to the duration of anti-
`inflammatory therapy, measured by the number of index med-
`ication refills.
`The likelihood of adherence was evaluated through multivari-
`ate logistic regression models. By using adherence as the dichoto-
`mous outcome, models controlled for patient age, hypertension,
`diabetes mellitus, prior cardiovascular conditions, previous PUD,
`previous ulcer/upper-GI bleed, number of concomitant medica-
`tions, and the number of index medication refills.
`After accounting for prior risk, concomitancy, and adher-
`ence, the primary end points of interest examined by the study
`were PUD (ICD-9-CM code 533.xx), ulcer, and/or upper-GI
`bleed (ICD-9-CM codes 531.xx, 532.xx, 534.xx, and 578.xx)
`occurring up to 12 months after the index prescription date.
`
`Descriptive analyses determined crude rates of predefined end
`points based on ICD-9-CM codes; univariate analyses examined
`the entire sample and ␹2 analyses compared the rates between
`ns-NSAID and coxib cohorts.
`We also examined the predefined GI events for the ns-NSAID
`and coxib cohorts as a function of adherence. To do so, the
`number of GI events within each patient cohort was normalized
`by dividing the sum of events by the cumulative sum of total
`days’ supply for the index medication; rates were expressed in
`patient-years. Rates of GI events per patient-year were plotted
`against levels of adherence for the ns-NSAID and coxib cohorts.
`Finally, multivariate analyses modeled the impact of 80% or
`greater adherence on the likelihood of GI events. The depen-
`dent variable was occurrence of PUD, ulcer, and/or upper-GI
`bleed during the ns-NSAID/coxib treatment period. The ns-
`NSAID/coxib treatment period was defined as the duration
`between the initial and final index medication prescription plus
`days’ supply for the last prescription or 12 months after the
`index prescription, whichever occurred first. Adherence was the
`independent variable of interest; the models also controlled for
`patient age, sex, and prior GI risk factors (previous PUD, esoph-
`agitis/gastroesophageal reflux disease, ulcer/upper-GI bleed,
`and gastritis) diagnosed within 12 months before the index
`ns-NSAID and coxib prescription. Logistic models evaluated
`ns-NSAID and coxib cohorts separately.
`Based on data from other trials and reports, patients with
`prior diagnoses of cardiovascular ischemic events are likely to
`be given aspirin for secondary prophylaxis.44 – 47 Because the
`data could not capture over-the-counter aspirin use reliably, we
`conducted an exploratory and post hoc analysis using coded
`cardiovascular diagnoses as a proxy measure for aspirin use to
`determine its impact on the likelihood of predefined GI out-
`comes. The analysis compared the rate of GI events among
`patients with cardiovascular disease diagnosed within 12
`months before the index ns-NSAID/coxib date against the rate
`among patients without diagnosed cardiovascular disease. Car-
`diovascular conditions included ischemic heart disease (ICD-
`9-CM codes 410.xx and 411.xx, excluding 411.1x and 414.xx),
`angina (ICD-9-CM codes 411.1x and 413.xx), stroke (ICD-9-CM
`codes 430.xx– 438.xx), and peripheral vascular disease (ICD-
`9-CM codes 443.8, 443.89, and 443.9). Multivariate logistic
`analyses modeled the likelihood of GI events in addition to the
`presence of cardiovascular disease; the model also controlled for
`patient age, the presence of hypertension and/or diabetes, prior
`PUD and/or ulcer, the number of concomitant medications
`during the anti-inflammatory treatment period, and the num-
`ber of index product refills.
`
`Results
`Patient Sample
`After all inclusion and exclusion criteria were applied,
`144,203 patients were available for analysis (Table 1). Of these,
`92,833 (64%) were treated with ns-NSAIDs and 51,370 (36%) were
`treated with coxibs. The most common ns-NSAID medications
`were naproxen and ibuprofen, comprising 37% and 32% of the
`patient sample, respectively. Other ns-NSAIDs included nabum-
`etone (8%), diclofenac sodium (6%), etodolac (4%), piroxicam (4%),
`oxaprozen (3%), and sulindac (2%). All other ns-NSAID products
`were used by fewer than 2% of patients. Approximately 53% of
`coxib patients were prescribed rofecoxib and 47% were treated with
`
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`1340 GOLDSTEIN ET AL
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`CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 11
`
`Table 1. Patient Demographics by Index Prescription and Concomitant Therapy
`
`ns-NSAIDs (n ⫽ 92,833; 64%)
`
`Coxibs (n ⫽ 51,370; 36%)
`
`Concomitant
`
`Nonconcomitant
`
`Concomitant
`
`Nonconcomitant
`
`Total n ⫽ 144,203
`
`Patients, n (%)
`Mean age, y (SD)
`Age, n (%)
`19–35 y
`36–45 y
`46–55 y
`56–65 y
`⬎65 y
`Female, n (%)
`Male, n (%)
`
`1312 (1.4a)
`48.40 (12.06)
`
`176 (13.41)
`332 (25.30)
`453 (34.53)
`271 (20.66)
`80 (6.10)
`815 (62.12)
`497 (37.88)
`
`91,521 (98.6)
`47.04 (11.46)
`
`14,227 (15.55)
`25,368 (27.72)
`31,089 (33.97)
`17,184 (18.78)
`3653 (3.99)
`53,777 (58.76)
`37,737 (41.23)
`
`1322 (2.6a)
`50.24 (10.86)
`
`120 (9.08)
`278 (21.03)
`515 (38.96)
`343 (25.95)
`66 (4.99)
`833 (63.01)
`489 (36.99)
`
`50,048 (97.4)
`50.59 (10.26)
`
`4080 (8.15)
`10,576 (21.13)
`19,323 (38.61)
`13,449 (26.87)
`2620 (5.23)
`30,936 (61.81)
`19,110 (38.18)
`
`144,203 (1.8)
`48.32 (9.66)
`
`18,603 (12.90)
`36,554 (25.35)
`51,380 (35.63)
`31,247 (21.67)
`6419 (4.45)
`86,361 (59.89)
`57,833 (40.11)
`
`aThe difference in the proportion of concomitant patients between ns-NSAID and coxib cohorts is statistically significant with a P value of .003.
`
`celecoxib. Less than 1% of the study population received valde-
`coxib. For details on health status by index prescription and
`concomitant therapy, see Supplemental Table 1 (supplementary
`material online at www.cghjournal.org).
`
`Likelihood of Initiating Concomitant
`Gastroprotective Agent Therapy
`Only 1.8% (n ⫽ 2634) of the total sample population
`initiated concomitant PPI or H2RA therapy within 14 days of
`the index ns-NSAID/coxib prescription (Table 2). Interestingly,
`coxib patients were more likely to receive GPAs compared with
`ns-NSAID users. Rates of concomitancy were 2.6% among
`coxib-treated patients and 1.4% in NSAID-treated patients
`(odds ratio [OR], 1.82; 95% confidence interval [CI], 1.69 –1.96).
`With respect to GPA therapy, 62% of patients received PPI
`therapy and 38% were treated with H2RAs. Variations were
`noted based on the index treatment cohort: patients treated
`with coxibs were more likely to be prescribed PPIs than H2RAs
`(74% vs 26%; P ⬍ .0001), whereas patients treated with ns-
`NSAIDs were equally as likely to be prescribed either therapy
`(50% each). Regression analysis further confirmed that patients
`treated with coxibs were more likely to initiate concomitant
`PPI/H2RA treatment than patients treated with ns-NSAIDs
`(OR, 1.31; 95% CI, 1.26 –1.35) (Table 3).
`
`Impact of Gastrointestinal Risk Factors on
`Concomitant Gastroprotective Agent Therapy
`As shown in Table 2, a significantly higher proportion
`of concomitant patients within both the ns-NSAID and coxib
`cohorts had prior GI diagnoses compared with nonconcomi-
`tant patients (P ⬍ .0001). Furthermore, prior GI diagnoses were
`more common among concomitant coxib users compared with
`concomitant ns-NSAID users (22.8% vs 12.3%; P ⬍ .0001). In
`general and consistent with these results, the multivariate anal-
`ysis found that patients at increased risk of GI events were more
`likely to initiate concomitant therapy (Table 3). The probability
`of concomitancy was 38% higher for patients aged older than 65
`years compared with those aged 36 – 45 years (OR, 1.38; 95% CI,
`1.27–1.50), 36% higher for patients with a previous ulcer diag-
`nosis (OR, 1.36; 95% CI, 1.20 –1.54), 26% higher for patients
`with concomitant oral steroid use (OR, 1.26; 95% CI, 1.20 –
`1.33), and 62% higher for patients undergoing concomitant
`anticoagulant therapy (OR, 1.62; 95% CI, 1.42–1.84).
`Among ns-NSAID users, concomitancy rates did not vary
`significantly according to the presence of multiple GI risk
`factors and ranged from 1.4% among patients with no risk
`factors to 2.1% among patients with at least 2 risk factors.
`Similarly, concomitant
`therapy rates remained consistent
`across all levels of risk for patients treated with coxibs (no risk
`factors, 2.6%; 1 risk factor, 2.5%; 2 risk factors or more, 2.4%).
`
`Table 2. Prior GI Diagnoses by Index Prescription and Concomitant Therapy
`
`Patients, n (%)
`PPI prescription, n (%)
`H2RA prescription, n (%)
`GI events during 12-month preperiod, n (%)
`PUD
`Esophagitis
`Ulcer/upper-GI bleed
`Gastritis
`Any GI events, n (%)
`
`aP ⬍ .0001 vs nonconcomitant therapy.
`
`ns-NSAIDs
`
`Coxibs
`
`Concomitant
`
`Nonconcomitant
`
`Concomitant
`
`Nonconcomitant
`
`1312 (1.4)
`656 (50)
`656 (50)
`
`9 (0.7)a
`103 (7.9)a
`23 (1.8)a
`53 (4.0)a
`161 (12.3)a
`
`91,521 (98.6)
`—
`—
`
`93 (0.1)
`1147 (1.3)
`1035 (1.1)
`713 (0.8)
`2774 (3.0)
`
`1322 (2.6)
`978 (74)
`344 (26)
`
`17 (1.3)a
`207 (15.7)a
`50 (3.8)a
`70 (5.3)a
`302 (22.8)a
`
`50,048 (97.4)
`—
`—
`
`96 (0.2)
`1136 (2.3)
`799 (1.6)
`593 (1.2)
`2355 (4.7)
`
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`ADHERENCE TO GASTROPROTECTIVE THERAPY 1341
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`Table 3. Logistic Regression Results: The Likelihood of
`Initiating Concomitant Therapy
`
`Table 4. Logistic Regression Results: Predicting Adherence
`With Concomitant PPI Therapy
`
`Independent variable
`
`Coxibs
`Age, y
`19–35
`46–55
`56–65
`⬎65
`Female
`Previous PUD
`Previous esophagitis/GERD
`Previous ulcer/upper-GI bleed
`Previous gastritis
`Previous oral steroid use
`Pre-/postanticoagulant use
`
`Reference
`group
`
`OR
`
`95% CI
`
`Independent variable
`
`Reference
`group
`
`OR
`
`95% CI
`
`ns-NSAIDs
`
`1.31
`
`1.26–1.35
`
`36–45 y
`36–45 y
`36–45 y
`36–45 y
`Male
`—
`—
`—
`—
`—
`—
`
`1.04
`1.12
`1.18
`1.38
`1.25
`2.46
`3.78
`1.36
`2.46
`1.26
`1.62
`
`0.98–1.10
`1.07–1.17
`1.12–1.24
`1.27–1.50
`1.21–1.30
`1.81–3.34
`3.47–4.12
`1.20–1.54
`2.17–2.78
`1.20–1.33
`1.42–1.84
`
`Age, y
`19–35
`46–55
`56–65
`⬎65
`Hypertension
`Diabetes mellitus
`Cardiovascular condition
`Previous PUD
`Previous ulcer/upper GI-bleed
`Number of concomitant medications
`Number of index medication refills
`
`36–45 y
`36–45 y
`36–45 y
`36–45 y
`—
`—
`—
`—
`—
`—
`—
`
`1.17 0.78–1.75
`1.43 1.08–1.89
`1.06 0.78–1.45
`0.81 0.48–1.36
`0.87 0.67–1.14
`1.20 0.83–1.75
`1.02 0.67–1.55
`1.06 0.42–2.69
`1.62 0.84–3.12
`0.90 0.87–0.94
`0.97 0.94–0.99
`
`However, regardless of the level of risk, rates of coprescribed
`GPA therapy remained low.
`
`Impact of Adherence on Patient Outcomes
`For the purposes of evaluating the impact of adherence
`in reducing the occurrence of clinically significant upper-GI
`events, we limited our analysis to the concomitant use of PPIs
`only, resulting in a sample size of 1643 patients: 664 (40%) were
`treated with ns-NSAIDs and 979 (60%) were treated with coxibs.
`As shown in Figure 1, there was a tendency for patients to be
`less adherent with GPA therapy as the duration of anti-inflam-
`matory treatment increased (as measured by the number of
`refills of their anti-inflammatory therapies). These results are
`confirmed in Table 4, which shows that adherence decreases
`significantly with increasing numbers of index prescription
`refills (OR, 0.97; 95% CI, 0.94 – 0.99). The likelihood of adher-
`ence also decreases as patients increase the number of any
`concomitant medications (OR, .90; 95% CI, 0.87– 0.94). Recog-
`nized risk factors for ulcer complications did not influence the
`likelihood of adherence.
`
`Collectively, 68% of ns-NSAID and coxib patients had adher-
`ence of 80% or greater over the entire duration of their days’
`supply of anti-inflammatory drugs. Figures 2 and 3 show the
`unadjusted rates of GI events per patient-year across increasing
`levels of adherence. Among ns-NSAID users, the likelihood of
`GI complications decreases as adherence increases (Figure 2,
`R2 ⫽ 0.3088). In comparison, GI event rates remain relatively
`constant across all adherence levels for coxib patients (Figure 3,
`R2 ⫽ 0.0079). Among ns-NSAID users, patients with less than
`80% adherence were nearly 2.5-fold more likely to experience
`upper-GI events during therapy compared with patients with 80%
`or greater adherence (OR, 2.38; 95% CI, 1.02–5.56) (Table 5).
`Multivariate analyses confirmed that adherence to PPI therapy
`did not influence the likelihood of GI injury among the coxib
`cohort. Other factors found to influence the incidence of GI
`complications included previous PUD for ns-NSAID patients
`(OR, 19.62; 95% CI, 3.23–119.37) and previous ulcer/upper-GI
`bleed for coxib patients (OR, 6.22; 95% CI, 2.75–14.07).
`The post hoc analysis using cardiovascular diagnoses as a
`possible proxy for aspirin use found that patients with a pre-
`vious cardiovascular diagnosis had a significantly higher rate of
`
`Figure 1. Percent adherence by number of index medication refills.
`
`, Adherence 80% or greater;
`
`, adherence less than 80%.
`
`Patent Owners' Ex. 2065
`IPR2018-00272
`Page 5 of 10
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`

`1342 GOLDSTEIN ET AL
`
`CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 4, No. 11
`
`Figure 2. Number of GI events per patient-year by
`level of adherence in the ns-NSAID cohort.
`
`GI complications when compared with patients without any
`prior cardiovascular risk (10% vs 5%; P ⫽ .0084). However, the
`population at risk was small, with only 120 patients having
`prior cardiovascular disease. Therefore, the inferences that can
`be made based on these data are limited.
`
`Discussion
`This study was designed to evaluate physician and pa-
`tient behavior with regard to long-term anti-inflammatory ther-
`apy. Specifically, this study evaluated the impact of adherence
`with GPA therapies on clinically relevant upper-GI outcomes
`among patients receiving ns-NSAIDs. Our results show that
`reductions in adherence with coprescribed GPA therapies in
`patients taking ns-NSAIDs are associated with linear increases
`in the rate of coded end points of upper-GI events, and that lack
`of adherence increases the rate of upper-GI events 2.5-fold in
`the population studied.
`Furthermore, our results indicate that among patients at
`higher risk for NSAID-associated gastroduodenal injury (age
`65 y or older, previous GI complication, or prior oral steroid or
`anticoagulant use), less than one third are treated with either a
`coxib or concomitantly with an ns-NSAID plus a PPI or even an
`H2RA. These results are not dissimilar from those reported by
`Abraham et al.27 A previous analysis showed that even among
`subpopulations of patients at higher risk, the level of interven-
`tion is inadequate, ranging from 36% of patients with at least 1
`
`risk factor to only 54% with all 3 risk factors.48 Moreover, even
`when protective therapy is initiated, it often is suboptimal.
`Among the patients receiving concomitant therapy, approxi-
`mately 62% are prescribed the recommended PPIs,
`leaving
`nearly 38% to be treated with the less-effective H2RAs.
`Although these data are consistent with findings by other
`investigators,27 an additional unexpected observation was
`seen in our analysis. We noted that more than half of pa-
`tients receiving a PPI were treated concomitantly with a
`coxib. Although these results may suggest that when risks are
`recognized physicians may act more cautiously by prescrib-
`ing multiple protective therapies, they equally suggest pos-
`sible overuse of these protective therapies. Although our
`study shows no advantage of adding a PPI to existing coxib
`therapy (Figure 3), our findings may not be generalizable to
`all populations. For example, Rahme et al49 reported a ben-
`efit of adding a PPI to patients receiving coxibs in 2 patient
`populations, those aged 75 years and older, and those receiv-
`ing concomitant aspirin. More recently, a preliminary report
`by Chan et al50 in patients who had previously sustained an
`upper-GI ulcer bleeding episode while using NSAIDs, re-
`vealed a significant reduction in the rate of recurrent ulcer
`bleeding in this unique high-risk population receiving es-
`omeprazole 20 mg twice a day plus celecoxib 200 mg twice a
`day compared with celecoxib alone. Thus, it is possible that
`concomitant coxib and PPI therapy may offer clinically sig-
`
`Figure 3. Number of GI events per patient-year by
`level of adherence in the coxib cohort.
`
`Patent Owners' Ex. 2065
`IPR2018-00272
`Page 6 of 10
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`November 2006
`
`ADHERENCE TO GASTROPROTECTIVE THERAPY 1343
`
`Table 5. Logistic Regression Results: Impact of Adherence on Likelihood of Upper-GI Events
`
`ns-NSAIDs
`
`Coxibs
`
`Independent variable
`
`Reference group
`
`OR
`
`95% CI
`
`Adherence ⱕ80%
`Age, y
`19–35
`46–55
`56–65
`⬎65
`Female
`Previous PUD
`Previous esophagitis/gastroesophageal reflux disease
`Previous ulcer/upper-GI bleed
`Previous gastritis
`
`Adherence ⱖ80%
`
`2.38
`
`1.02–5.56
`
`36–45 y
`36–45 y
`36–45 y
`36–45 y
`Male
`N/A
`N/A
`N/A
`N/A
`
`2.07
`1.13
`1.65
`2.14
`.71
`19.62
`.56
`5.75
`.84
`
`.46–9.31
`.36–3.59
`.47–5.76
`.36–12.87
`.30–1.66
`3.23–119.37
`.12–2.70
`.96–34.44
`.14–5.14
`
`OR
`
`1.12
`
`2.27
`1.92
`.89
`1.95
`1.13
`6.04
`1.54
`6.22
`2.25
`
`95% CI
`
`.61–2.07
`
`.75–6.83
`.81–4.55
`.32–2.50
`.54–7.08
`.62–2.03
`1.78–20.44
`.80–2.97
`2.75–14.07
`.91–5.53
`
`nificant benefits to patients at particularly high risk; how-
`ever, this was not the population studied in the current
`analysis.
`The question then arises whether concomitant GPA therapy
`is effective in reducing the risk of upper-GI events among
`patients continuing to use long-term anti-inflammatory treat-
`ment. Although endoscopic and outcomes studies have shown
`that GPA therapy appears to be protective against upper-GI
`ulcer complications associated with ns-NSAIDs,8,11,42 few stud-
`ies have examined the level of