Article, Gastroenterology

Rising rates of proton pump inhibitor prescribing in US emergency departments

a b s t r a c t

Objective: There have been mounting safety concerns over increasing prescription rates for proton pump inhibitors (PPIs). Trends in PPI use have not been studied in emergency departments (EDs). We characterize trends in PPI use in US EDs.

Methods: We used data from the National Hospital Ambulatory Care Survey, from 2001 to 2010, focusing on encounters with a reason for visit with a potential indication for a PPI, histamine receptor (H2) blocker, or antacid. Patient, provider, visit, and hospital-level factors associated with increases in PPI use were evaluated. Results: Among included visits, ED PPI prescribing more than doubled from 3.0 (95% confidence interval [CI]: 2.4-3.8) to 7.2% (95% CI: 6.3-8.3) from 2001 to 2010. Histamine receptor blocker use decreased from 6.8% (95% CI: 6.0-7.7) to 5.7% (95% CI: 4.9-6.7) and antacids from 7.2% (95% CI: 6.3-8.2) to 5.5% (95% CI: 4.8-6.3). Proton

pump inhibitor prescribing was higher in males and whites yet increased across all demographics, including in adults aged 65 years and older. Proton pump inhibitor prescribing increased significantly in all US regions and across all hospital and payer types. Pantoprazole was the agent with the largest increase in use.

Conclusions: Over the past decade, there have been considerable increases in PPI prescribing in US EDs. This trend occurred despite rising safety concerns, even in populations at higher risk for adverse events such as older adults. More education may be needed to ensure that ED providers are familiar with indications for PPIs.

(C) 2014

Introduction

Proton pump inhibitors (PPIs) are one of the most commonly prescribed Classes of PHarmaceuticals, with an estimated 113 million prescriptions filled annually in the United States [1]. Proton pump inhibitors are used for a variety of indications including gastroesoph- ageal reflux disease (GERD), esophagitis, gastritis, Peptic ulcer disease (PUD), and hypersecretory states. In addition, they are used for stress ulcer prophylaxis and to prevent Bleeding complications in patients on medications such as nonsteroidal antiinflammatory drugs (NSAIDs),

? Funding Support: No funding support was provided for this study.

?? Financial Disclosures: The authors have no financial relationships relevant to

this article to disclose.

??? Conflict of Interest: The authors have no conflicts of interest to disclose.

? Abstract accepted for presented in poster form at the American Society for Clinical

Pharmacology and Therapeutics Annual Meeting, Atlanta GA, March 2014 and as a platform presentation at the Society for Academic Emergency Medicine Annual Meeting, Dallas TX, May 2014.

* Corresponding author. 111 Michigan Ave NW, Washington, DC 20010.

E-mail address: [email protected] (M. Mazer-Amirshahi).

Antiplatelet agents, and anticoagulants [2]. Despite their widespread use and perceived safety, PPIs have recently been associated with several severe adverse effects, including osteoporosis and Associated fractures, hypomagnesemia, community-acquired pneumonia, and Clostridium Difficile colitis [2-6]. There have also been concerns regarding the development of gastric polyps and carcinogenesis [3]. Finally, some PPIs have significant drug-Drug interactions. For example, use of omeprazole in patients taking clopidogrel has been associated with adverse cardiovascular outcomes due to decreased metabolic activation of the antiplatelet agent [7].

Existing data suggest that PPIs are overprescribed in many settings [8]. Up to two-thirds of patients prescribed PPIs as inpatients in the hospital do not have an appropriate indication [9]. In addition, patients who are started on PPIs in the hospital are often continued on them after discharge, even in the absence of a therapeutic indication [10]. This can translate into increased health care expenditures, as almost $14 billion a year is spent on PPIs in the United States alone [2]. prescribing patterns of PPIs have been described in the primary care and in-hospital settings; however, emergency department (ED) use of PPIs have not been characterized using national-level data. Overuse

http://dx.doi.org/10.1016/j.ajem.2014.03.019

0735-6757/(C) 2014

of PPIs in the ED setting could have significant implications because PPIs have a delayed onset of action (up to 24 hours for peak effect), PPIs cost more than therapeutic alternatives, and the medication may be continued beyond the acute setting, which can lead to long-term adverse effects [10,11].

In this study, we report trends in PPI use compared with therapeutic alternatives in adult patients in US EDs over time. The primary hypothesis was that there would be a significant increase in ED PPI prescribing during the study period, which would mirror increases in PPI prescribing reported in other settings.

Methods

This is a retrospective review of publicly available data from the National Hospital Ambulatory Medical Care Survey from 2001 to 2010. The National Hospital Medical Ambulatory Care Survey is an annual, multistage probabilistic sample of visits made to US EDs conducted by the Centers for Disease Control and Prevention, Centers for National Health Statistics. The survey is designed to collect information about the utilization and provision of services by hospital- based EDs. A multistage weighted sampling design is used, from which national-level estimates for ED visits can be derived. We did not perform an a priori power analysis to determine an appropriate sample size as the number of samples in the NHAMCS database is very large, with a total unweighted sample size of 357 681 visits for the study period [12]. This was not human subject research and was exempt from institutional review board review.

We classified all medications administered in the ED and prescribed at discharge, specifically focusing on PPIs and therapeutic alternatives to PPIs. Therapeutic alternatives to PPIs include histamine receptor antagonists (H2 blockers) and traditional antacids and topical therapies, such as calcium carbonate. A single author (MMA) who is board certified in emergency medicine and toxicology and is also a registerED pharmacist performed all medication coding. A comprehensive list of specific medications is included in a Supplemental Appendix.

The sample was restricted to visits involving patients aged 18 years and older and included common gastrointestinal complaints and reasons for visit during which acid suppressing medication or antacid might be prescribed. These reasons for visit were identified by the same author who performed medication coding. In NHAMCS, up to 3 reasons for visit are documented for each visit. Visits with one or more of these reasons for visits were included.

Additional patient demographic data analyzed included age 65 years and older, sex, race, and source of payment (Medicare, Medicaid, self-pay, private, and other). Visit-level factors examined included reason for visit, patient disposition (admitted vs discharged), and type of provider (attending, resident, or midlevel provider). hospital characteristics such as geographic region, metropolitan statistical area, and hospital type (for profit, nonprofit, or government, and teaching vs nonteaching) were also explored.

We tabulated the proportion of encounters with potential indications during which each of the drug classes was prescribed in the ED or at discharge and each specific PPI for each year. For 2005 to 2010, NHAMCS included additional data on whether medications were administered in the ED or prescribed at discharge. For these years, separate analyses were performed to discriminate between ED prescribed vs medications prescribed at discharge. We used a ?2 test with Stata 12 (Stata Corp. LP, College Station, TX) to assess the significance of trends over time. A P b .05 was considered significant.

Results

The weighted estimate of included ED visits increased from 20.1 million in 2001 to 28.3 million in 2010, representing 24.8% and 28.3% of visits in those years, respectively. Between 2001 and 2010, among included visits, ED prescribing of PPIs more than doubled from 3.0%

(95% confidence interval [CI]: 2.4-3.8) to 7.2% (95% CI: 6.3-8.3).

The use of H2 blockers decreased from 6.8% (95% CI: 6.0-7.7) to 5.7%

(95% CI: 4.9-6.7) and antacids from 7.2% (95% CI: 6.3-8.2) to 5.5%

(95% CI: 4.8-6.3).

Demographic differences

Proton pump inhibitor prescribing in patients aged 65 years and older increased from 3.3% (95% CI: 2.5-4.4) to 7.2% (95% CI: 5.5-9.2). Proton pump inhibitor prescribing was more common in males and demonstrated greater proportional increases in this group. Proton pump inhibitor use increased among all racial groups but to a greater extent in whites. Patients with a payment source of self-pay had the highest increase in PPI prescribing over the study period. Proton pump inhibitor use increased to a greater extent in visits, where the patient was admitted but also increased among discharges (Table 1).

Provider and hospital-level factors

Visits during which a resident or midlevel provider compared with an attending evaluated the patient had higher rates of and greater increases in PPI prescribing. At the same time, all 3 provider groups had significant increases in PPI prescribing over the 10-year study period. Proton pump inhibitor prescribing rates increased throughout all regions but were greatest in the western United States. Proton pump inhibitor use increased the most in urban and government hospitals, but the use of PPIs remained greater overall in nonurban and for-profit hospitals. Hospitals that were teaching institutions had larger increases in PPI prescribing compared with nonteaching institutions (Table 1).

Table 1

Demographic characteristics of ED visits during which a PPI was administered/prescribed

Characteristic

2001

2010

Percent change

P

Patient

Age >= 65 y

3.3% (2.5-4.4)

7.2% (5.5-9.2)

115.3%

.001

Sex

Male

2.8% (2.1-3.8)

7.7% (6.4-9.1)

169.4%

.001

Female

3.1% (2.4-4.1)

7.0% (5.9-8.2)

122.4%

.001

Race

White

2.9% (2.3-3.5)

7.4% (6.4-8.6)

157.8%

.001

Black

3.4% (1.8-6.3)

6.2% (4.9-7.8)

83.9%

.001

Other

4.7%a

9.7% (6.5-14.2)

106.8%

a

Disposition

Admitted

2.4% (1.7-3.4)

9.3% (7.6-11.4)

290.0%

.001

Discharged

3.2% (2.5-4.1)

6.6% (5.6-7.9)

106.5%

.001

Source of payment

Private insurance

3.1% (2.3-4.3)

8.6% (7.1-10.4)

172.9%

.001

Medicaid

3.8% (2.5-5.7)

6.3% (5.1-7.7)

66.7%

.003

Medicare

3.4% (2.4-4.9)

7.4% (5.8-9.4)

116.1%

.003

Self-pay

2.1% (1.2-3.5)

6.5% (5.1-8.4)

216.0%

.001

Provider

Attending

3.1% (2.4-4.0)

6.9% (6.0-8.1)

122.4%

.001

Resident

2.6% (1.6-4.1)

7.4% (5.4-10.0)

185.0%

.001

Midlevel provider

2.1% (0.9-5.2)

9.5% (6.7-13.4)

344.9%

.001

Hospital

Geographic region

Northeast

3.0% (2.5-3.7)

7.3% (5.7-9.3)

141.9%

.001

Midwest

3.1% (1.8-5.2)

6.8% (4.9-9.4)

122.8%

.049

South

3.0% (1.9-4.6)

6.7% (5.4-8.4)

126.6%

.001

West

3.0% (2.1-4.4)

8.5% (6.3-11.4)

180.3%

.001

Location

Urban

2.7% (2.1-3.4)

7.1% (6.1-8.2)

162.2%

.001

Nonurban

4.5% (2.6-7.5)

8.0% (5.8-11.1)

80.0%

.091

Type

Nonprofit

3.0% (2.3-3.9)

7.0% (5.9-8.2)

130.0%

.001

Government

2.6% (1.3-5.0)

7.5% (6.0-9.4)

189.6%

.001

For profit

3.6% (2.2-5.8)

8.7% (6.2-12.1)

140.3%

.027

Teaching

2.2% (1.7-2.9)

8.3% (6.0-11.4)

275.9%

.001

Nonteaching

3.2% (2.5-4.1)

7.0% (6.1-8.0)

118.4%

.001

a Denotes sample size is too small make reliable comparison.

ED administration vs discharge prescriptions

For the years 2005 to 2010 when ED prescribed medications were differentiated from those prescribed at discharge, a greater increase in prescribing rates was found in PPIs administered in the ED than PPIs given as discharge prescriptions. Histamine receptor blocker administra- tion in the ED increased modestly, but discharge prescriptions declined. Antacid prescribing both in the ED and at discharge decreased (Table 2).

Specific agents

Over the study period, the use of all PPIs increased, but there were different patterns of use for individual agents. At the beginning of the study period, omeprazole was the most commonly prescribed PPI in the ED. Over time, esomeprazole and pantoprazole prescribing increased, with the most dramatic increase in pantoprazole use. We did not have adequate sample size to assess trends in other PPIs such as lansoprazole and rabeprazole (Fig.).

Prescribing patterns based on reason for visit

The most common reason for visit during which a PPI was prescribed was reported as “other symptoms of the abdomen and pelvis” (18.4%). Other common reasons included symptoms related to chest pain, gastrointestinal hemorrhage, gastrointestinal reflux, and gastritis. There was some overlap between H2 blockers and antacids. Of note, the second most common reason H2 blockers were prescribed was associated with Allergic reactions (7.6%). Interestingly, the top 5 reasons for visit only accounted for approximately half of the total prescribing for all 3 groups of medications, suggesting a significant amount of prescribing for nongastrointestinal indications.

Discussion

Proton pump inhibitors are one of the highest selling classes of drugs in the United States with more than 100 million prescriptions and $13.9 billion in sales in 2010 [13, 14]. Although ED prescribing rates were relatively low (which could have been related to the liberal inclusion of certain reasons for visit), our analysis demonstrated that the use of PPIs in US EDs has more than doubled from 2001 to 2010. This trend can a have significant implications when translated into millions of visits annually.

Similar to reasons that have driven increased PPI use in other settings, ED physicians may believe that PPIs are a superior therapeutic option. For certain indications such as PUD, Upper gastrointestinal bleeding, and severe or refractory GERD, PPI therapy has demonstrated superiority. On the other hand, the Risk-benefit profile for PPIs is less favorable for indications such as routine heartburn, gastritis, and uncomplicated GERD.

[15] It is unclear if our findings represent appropriate prescribing of PPIs, overuse, or a combination of the 2.

Overuse of PPIs has been well documented in other settings and is concerning because these medications are not as benign as previously thought. Studies have demonstrated associations between PPI use and osteoporosis, pneumonia, enteric infections, electrolyte abnormalities, and Drug-drug interactions [16, 17]. Even more concerning is that PPI

Table 2

Medications administered in the ED vs prescribed at discharge

Medication

2005

2010

Percent change

P

PPI in ED

2.3% (1.8-2.9)

4.5% (3.7-5.4)

94.8%

.001

PPI at discharge

2.2% (1.7-2.8)

2.8% (2.2-3.4)

26.6%

.001

H2 blocker in ED

3.5% (2.8- 4.3)

3.8% (3.1-4.6)

10.1%

.001

H2 blocker at discharge

1.5% (1.1-1.9)

1.5% (1.2-1.9)

1.4%

.001

Antacid in ED

5.7% (4.8-6.8)

4.6% (4.0-5.4)

-19.2%

.001

Antacid at discharge

1.1% (0.8-1.4)

0.7% (0.5-1.1)

-32.4%

.001

use increased significantly among patients aged 65 years and older who are at higher risk for the aforementioned adverse drug events and interactions.

The major concern regarding PPI drug-drug interactions centers around the CYP2C19 enzyme, which certain PPIs can inhibit. This may decrease the efficacy of medications such as clopidogrel, which is commonly used after cardiac stent placement [18]. The coadminis- tration of PPIs that inhibit CYP2C19 with clopidogrel can increase thrombotic risk [7, 19, 20]. At the same time, many of these patients are also at a higher risk of gastrointestinal bleeding, and current guidelines recommend gastrointestinal protectant therapy while on antiplatelet agents [21, 22]. One strategy to mitigate the risk of Stent thrombosis is to use either rabeprazole or pantoprazole in patients on clopidogrel because they have less affinity for CYP2C19 [21, 22]. Emergency department providers should review their patients’ medica- tion list and take these interactions into consideration when prescribing a PPI.

Another potential side effect of long-term PPI use that is particularly relevant to older adults is the increased risk of osteoporosis. The presumed mechanism for decreasing bone strength is due to the decreased absorption of B12 and calcium, which increase osteoblastic activity [16]. Although no definitive study is available, a meta-analysis of published observational and Case-control studies demonstrated a 30% increase in fractures in patients who use PPIs compared with those who do not use the medication [23]. Although these effects are not a major concern in the acute setting, prior studies in other settings have demonstrated that PPIs are often continued beyond the recommended duration of therapy [10].

The acidic environment of the stomach is designed to create an inhospitable milieu for bacterial growth. Long-term decreases in gastric acidity may lead to more enteric infections such as C difficile colitis. Although not conclusive, a meta-analysis of observational studies suggests that PPIs may lead to a 65% increase in the incidence of C difficile-associated diarrhea. [24] Some observers believe that the widespread use of PPIs may be contributing to the increase in C difficile in the community and in patients who have not been exposed to antibiotics [25, 26].

Among PPIs, there were different prescription patterns for individual drugs. In the ED, there was an increasing trend for both omeprazole and esomeprazole prescriptions at roughly the same rate (Fig.). The only chemical difference is that omeprazole contains mixed enantiomers, whereas esomeprazole contains only the S stereoisomer of the same molecule. However, omeprazole is less expensive and available without a prescription. The PPI with the greatest increase in ED use was pantoprazole, which may be due to the fact that pantoprazole was the first PPI available in an intravenous formulation and might be the preferred PPI on hospital formularies. As such, ED providers may be more familiar with pantoprazole. Differences in prescribing of individual agents could also be related to pharmaceutical marketing strategies.

Proton pump inhibitors are prescribed for different reasons in different medical settings. In the hospital, admitted patients could be prescribed a PPI for stress ulcer prophylaxis; in the outpatient setting, patients could be prescribed PPIs to treat more chronic conditions such as Helicobacter pylori infection or Barrett esophagus. However, in the ED, PPIs might be prescribed for symptomatic relief for the presenting complaint. The decision to preferentially prescribe PPIs over H2 blockers as a means to provide rapid relief for acid-related disease is questionable because of the different time to onset for the 2 classes of medication. Histamine receptor blockers work by competitive inhibition of the H2 receptors located on the surface of the parietal cells in the stomach. The effect of H2 blockers is to raise pH of the stomach within 1 hour [27, 28]. For PPIs, the mechanism of action is to enter the parietal cells and permanently inhibit the hydrogen pump within the cell. Although PPIs provide more potent inhibition of acid production and last longer than H2 blockers, several hours must elapse before PPIs raise gastric pH [11].

4.0%

3.5%

3.0%

2.5%

2.0%

1.5%

1.0%

0.5%

0.0%

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Pantoprazole Esomeprazole Omeprazole

Fig. Trends in specific PPI use over time.

Emergency department prescriptions tend to be for a Short duration, and the short-term use of a PPI is not associated with significant side effects. However, ED prescribing patterns are important because patients started on PPIs tend to stay on these medications for a long period of time [29]. Because of significant rebound acid production, PPIs may eventually cause the symptoms that they were initially designed to treat [30]. One study showed that a “step-up” approach to dyspepsia that begins with a trial of H2 blockers followed by PPIs if needed was more cost effective than a “step-down” approach that reverses the order [31].

Dyspepsia, gastritis, and gastric ulcers are common complaints in the ED. Proton pump inhibitors will provide effective symptomatic relief for these patients. One strategy to decrease the long-term use of PPIs after being treated in the ED is to treat the underlying cause. There are 2 main causes of dyspepsia, gastritis, and PUD: NSAIDs and H pylori infection. When possible, the offending medication should be discontinued. In addition, a targeted approach to managing H pylori infection including rapid H pylori testing in the ED may be feasible [32]. The treatment for H pylori has been shown to decrease long-term use of PPIs [33].

High PPI prescription rates have been recently highlighted by a campaign led by the American Board of Internal Medicine entitled choosing wisely (CW) [15]. The CW initiative is a partnership between the publication Consumer Reports and multiple specialty organizations to raise awareness of several patient-safety issues. Choosing Wisely has issued a statement regarding PPIs that addresses concerns that many patients with mild symptoms should not be on a PPI. The campaign highlights the increased cost of PPIs vs H2 blockers, the concern for drug interactions, the link to an increased risk of bone fractures, the risk of hypomagnesemia, and the risk of C difficile infections. For patients with mild disease, CW recommends diet and lifestyle changes and regular antacids as first-line therapy. This campaign is directed toward patients as well as physicians and is evidence that the PPI debate has moved passed the medical literature and into the layperson media.

Limitations

The main limitations of this study reflect the changing NHAMCS database over the study period and the use of survey administrative data for this type of analysis. The multistage sampling of the NHAMCS database is designed to make the sample representative, and the consistency and rigor of the NHAMCS methodology should protect against major inaccuracies. There may be minor inaccuracies because the sample is not a simple random sample, and there may be clustering of visits within hospitals and certain Geographic regions [34]. There can also be inaccuracies in specific variables. For example, determining race is challenging because race is typically recorded by an unrelated observer rather than by the patient and therefore may be misclassified. Other variables, such as pain scores are poorly populated in NHAMCS. There are also minor variations in individual variables, such as Diagnosis codes, from year to year [34].

The National Hospital Ambulatory Medical Care Survey is a national-level database that includes information pertaining to visits, not specific patients [12]. As such, it is not possible to review individual patient charts for further detail or to follow up patients longitudinally. Data regarding specific indication, dosing schedule, and duration of therapy are also not included in NHAMCS. Therefore, it is not possible to determine the appropriateness of PPI therapy or to evaluate associated outcomes or adverse effects. It is also not possible to determine whether the patient continued the medication beyond the initial ED prescription. Up to 8 medications can be recorded on the patient record, making it possible that some PPIs were discounted if the patient was given a greater number of medications. We could not differentiate between medications administered in the ED vs those prescribed at discharge for the early part of the study period (2001-2004), as these data were not divided by disposition during that time. The route of administration could not be investigated because this information is not available. Finally, for some years, we did not have adequate sample size to make reliable estimates to compare between different provider groups (attending, resident, and midlevel providers).

Conclusions

Our study found significant increases in PPI prescribing in the ED over the past decade, with a decline in utilization of therapeutic alternatives. This trend is concerning given the mounting evidence that has associated PPIs with several significant adverse effects and Drug-drug interactions. In addition, PPIs are not as effective for immediate symptomatic relief and are more expensive than Alternative agents. Emergency department providers should be familiar with the appropriate use of these medications and strive to prescribe them in a rationale and safe manner.

Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ajem.2014.03.019.

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