The American Journal of Managed Care October 2009
Impact of Compliance With Proton Pump Inhibitors on NSAID Treatment
Patients with gastroesophageal reflux disease who are compliant with proton pump inhibitor therapy stay on NSAIDs longer than noncompliant patients.
Objective: To assess the impact of patient compliance with proton pump inhibitor (PPI) therapy on nonsteroidal anti-inflammatory drug (NSAID) treatment duration and upper-gastrointestinal (GI) complications in patients with gastroesophageal reflux disease (GERD).
Study Design: Retrospective cohort study.
Methods: Study subjects were GERD patients receiving cotherapy with a PPI and a cyclooxygenase-2–selective (COX-2–selective) or nonselective NSAID. Patients compliant and noncompliant with PPI therapy were compared on NSAID treatment duration and incidence of upper-GI events.Kaplan-Meier analysis and a multivariate Cox proportional hazards model were used to compare durations of NSAID treatment, controlling for baseline characteristics. The incidences of GI events were compared using incidence rate and Poisson regression models. The analyses were conducted separately for patients taking COX-2–selective NSAIDs and those taking nonselective NSAIDs.
Results: In both patient groups taking a COX-2–selective agent (n = 12,562; 70.9% compliant) and nonselective NSAID (n = 17,487; 69.9% compliant), mean NSAID treatment duration was significantly longer (84.0 days and 20.8 days longer, respectively) in PPI-compliant patients than in noncompliant patients. Compliance with PPI therapy was associated with a greater reduction in the incidence of GI events than noncompliance in both patients taking a COX-2–selective NSAID (6-fold vs 5-fold; P = .026) and patients taking a nonselective NSAID (8-fold vs 6-fold; P = .002).
Conclusions: In GERD patients receiving NSAIDs, those who were compliant with PPI therapy had a longer NSAID treatment duration and better GI tolerability than those who were noncompliant.
(Am J Manag Care. 2009;15(10):681-688)
This study is the first to examine the effect of compliance with proton pump inhibitor (PPI) therapy on the duration of nonsteroidal anti-inflammatory drug (NSAID) treatment and gastrointestinal (GI) tolerability in patients with gastroesophageal reflux disease.
- Compliance with PPI therapy while patients are taking cyclooxygenase 2–selective (COX-2–selective) or nonselective NSAIDs is associated with longer NSAID treatment duration than noncompliance with PPI therapy.
- Compliance with PPI therapy while patients are taking COX-2–selective or nonselective NSAIDs is associated with better GI tolerability than noncompliance with PPI therapy.
Gastrointestinal (GI) adverse events are widely recognized as side effects of nonsteroidal anti-inflammatory drugs (NSAIDs).1,2 When left untreated, NSAID-related upper GI symptoms may lead to early treatment discontinuation,3 decreased quality of life,4,5 and increased healthcare resource use.6-8 In patients with gastroesophageal reflux disease (GERD), NSAIDs can worsen GERD symptoms,9 leading to suboptimal treatment with NSAIDs. Proton pump inhibitors (PPIs) are gastroprotective agents (GPAs) that have been shown to provide effective healing of upper-GI ulcers associated with nonselective NSAIDs.10 Proton pump inhibitors also have been shown to be effective in preventing the recurrence of such ulcers when coprescribed with NSAIDs.11,12
Several studies have reported that the success of an NSAID-GPA coprescription therapy in reducing ulcer complications depends on patients’ treatment adherence. Goldstein et al13 retrospectively evaluated the clinical impact of nonadherence to a GPA among NSAID users and found that nonadherence to the GPA (ie, adherence rates of <80%) was associated with a significantly higher risk of upper-GI ulcers/complications in nonselective NSAID users (odds ratio = 2.4; 95% confidence interval [CI] = 1.0, 5.6). Likewise, van Soest et al14 used data from a primary care electronic medical records database in the Netherlands and reported that the risk of a serious NSAID-related GI complication increased by 16% (95% CI = 2%, 32%) for every 10% decrease in GPA adherence (including histamine-2 receptor antagonist [H2RA] blockers, PPIs, and misoprostol) in high-risk patients who received both nonselective and cyclooxygenase-2–selective (COX-2–selective) NSAIDs. Findings from a retrospective observational study conducted by Sturkenboom et al15 showed that adherence to an NSAID plus a GPA (PPI or H2RA) was low (63%) and decreased over the length of NSAID use.
Although previous studies have investigated the impact of adherence to PPI-NSAID cotherapy on the incidence of GI complications in the general NSAID population, the present study assessed the association among GERD patients, the population susceptible to the GI toxicity of NSAIDs (potentially even COX-2 NSAIDs), and therefore likely to benefit from the gastroprotective effect of PPIs. The objectives of the study were 2-fold. First, we investigated whether compliance with PPI therapy would extend the duration of adherence to NSAIDs. Second, we assessed whether PPI compliance in cotherapy with NSAIDs would reduce the incidence of upper-GI adverse events. For both objectives, COX-2–selective and nonselective NSAID users were analyzed separately.
This study uses administrative health insurance claims data from the Ingenix Impact National Managed Care Database, developed by Integrated Health Care Information Solutions (Waltham, MA). This database contains complete medical history data for more than 25 million managed care lives in more than 30 health plans across all US census regions. Data elements include patient demographic characteristics, enrollment records, inpatient and outpatient diagnoses and procedures, and outpatient pharmacy dispensing claims.
A retrospective cohort design was used to compare outcomes between PPI-compliant and PPI-noncompliant GERD patients receiving NSAID therapy from January 2000 through February 2005 (Figure). Generic and brand-name prescriptions for esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole were included as PPI therapies; NSAIDs considered were COX-2–selective (celecoxib, rofecoxib, valdecoxib) or nonselective (eg, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac tromethamine, meclofenamate, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, sulindac, tolmetin). Patients were required to meet the following criteria for inclusion: continuous enrollment in a health plan for the time period identified in the study, ≥2 insurance claims with a GERD diagnosis (International Classification of Diseases, Ninth Revision, Clincial Modification [ICD-9-CM] diagnosis codes 530.1x, 530.81, 787.1), ≥90 days of health insurance eligibility before the first GERD claim (GERD index date), age ≥18 years at the first dispensing of a PPI, and ≥1 episode of NSAID therapy with the concomitant use of a PPI after the first GERD claim, where concomitance was defined as an overlap of at least 1 day between NSAID and PPI days of drug supplies. Patients who had used PPIs before their GERD index date were excluded. The unit of observation in the study was the NSAID treatment episode, and only those episodes with concomitant use of a PPI were included in the analysis. For example, if a patient had 2 NSAID treatment episodes, 1 with concomitant PPI use and 1 without PPI use, only the treatment episode with concomitant PPI use was analyzed. In this example, the PPI episode was used to assess PPI compliance status, as described in the section below. The PPI index date was defined as the date of the first PPI dispensing after the GERD index date.
Definition of Compliance With PPI Cotherapy
To measure PPI compliance, patients had to have a continuous period of PPI therapy with at least 2 PPI prescription dispensings. Specifically, a patient had to have (1) at least 1 PPI episode, which is defined as a continuous period of PPI therapy with no interruption of more than 56 days in drug supply, and (2) at least 2 PPI dispensings within an episode, which enabled measurement of patient compliance. Patient-level PPI compliance was calculated using the medication possession ratio (MPR), defined as follows:
MPR = days of PPI supply/days between date of first prescription and drug supply end date of the last refill.
The numerator of this ratio is the total days of PPI prescription drug supplied, including covered days from all refills. The denominator is the intended treatment duration, calculated as the number of days between the first and last refill date plus supply days of the last refill.16 If a patient had more than 1 PPI episode, the MPR was calculated as the sum of the supply days in each episode divided by the sum of the durations in each episode. Using the standard methodology, an MPR >80% was considered to represent PPI compliance, and an MPR ≤80% was considered to represent PPI noncompliance.17,18
Patient demographic information (eg, age, sex) and health plan type (eg, health maintenance organization, point-of-service, preferred provider organization) were assessed on the date of the first PPI claim. ICD-9-CM codes
were used to identify comorbidities associated with GERD,including cough, asthma, sleeplessness, dyspepsia, and dysphagia,19-22 and for history of GI (duodenal, gastric, or peptic) ulcers. The Charlson comorbidity index was calculated as an indicator of general health state.23 Comorbidities related to GERD, history of GI ulcers, and the Charlson comorbidity index were assessed based on claims up to 180 days before the PPI index date. Finally, a compliance behavior indicator, general compliance, was introduced to control for underlying general behavioral differences in medication compliance across the compliant and noncompliant groups to isolate the compliance effect specifically related to PPI therapy. This measure was established based on patients’ compliance with 3 common long-term therapies used to treat chronic diseases (diabetes mellitus, hypertension, and hypercholesterolemia), using the previously described MPR calculation. The general compliance indicator was determined using all data available prior to baseline because it was intended to measure the general behavior of the patient as opposed to the patient’s health status at the beginning of the study. For patients without any of the identified chronic diseases, a separate category of “unknown” was assigned to their general compliance value.
Definition of Outcome Measures
Two outcome measures of interest were compared in the PPI-compliant and PPI-noncompliant groups: NSAID treatment duration and the incidence rate of upper-GI events. Upper-GI events included peptic ulcer disease (ICD-9-CM 533), disease of the esophagus (ICD-9-CM 530) except esophagitis (ICD-9-CM 530.1) and esophageal reflux (ICD-9-CM 530.81), upper-GI bleed (ICD-9-CM 531, 532, 534, 578), and gastritis and duodenitis (ICD-9-CM 535). We specifically excluded esophagitis and esophageal reflux because these were already used to identify the population with GERD.
For each patient, the use of a COX-2–selective or nonselective NSAID was divided into treatment episodes, defined as continuous periods of therapy with no interruption of more than 28 days in drug supplies. Therefore, 1 patient could have more than 1 episode eligible for analysis. For each NSAID treatment episode, the NSAID treatment duration was defined as the number of days from the date of initiation of NSAID treatment to the end of supply days of the last NSAID dispensing.
To measure the impact of PPI compliance on GI tolerability during NSAID use, each treatment episode was divided into 2 periods: the pre-PPI period (the start of the NSAID treatment episode to the first day of PPI dispensing in that episode) and the post-PPI period (the first day of PPI dispensing to the end of the NSAID treatment episode). The incidence rate of GI events before PPI initiation was higher for PPI-compliant patients than for PPI-noncompliant patients. Therefore, the GI incidence rates in the post-PPI period were benchmarked against those in the pre-PPI period by calculating the ratio of the pre-PPI incidence rate over the post-PPI incidence rate (IRR) for both the PPI-compliant and PPI-noncompliant groups. The incidence rate of GI events was defined as the number of GI-related events per person per year, to adjust for varying observation lengths in an observational setting. Multiple GI diagnoses recorded on the same day were considered a single event.
Baseline characteristics of the compliant and noncompliant PPI groups were summarized descriptively. The difference in NSAID treatment duration between PPI-compliant and PPI-noncompliant groups was determined using Kaplan-Meier survival analysis and multivariate Cox proportional hazards models. The multivariate proportional hazards modelincluded the following baseline covariates for adjustment: age, sex, health plan type, GERD-related comorbidities (ie, cough, asthma, sleeplessness, dyspepsia, dysphagia), history of GI ulcer, Charlson comorbidity index, and general compliance. Because general compliance could not be assessed for all patients, we introduced an additional dummy variable for missing data that took a value of 1 when general compliance could be assessed and zero otherwise. The dummy variable permits the inclusion of all patients in the analysis by assigning those with missing values to a separate category instead of deleting them. The expected NSAID treatment duration based on the proportional hazards model was estimated as the area under the resulting survival curve. A 95% CI around this measure was calculated using a bootstrap approach.24