Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus.

C L I N I C A L F E AT U R E S

Aspirin and Proton Pump Inhibitor Combination Therapy for Prevention of Cardiovascular Disease and Barrett’s Esophagus

Postgraduate Medicine Downloaded from informahealthcare.com by Nyu Medical Center on 04/14/15 For personal use only.

DOI: 10.3810/pgm.2014.01.2728

David A. Peura, MD 1 C. Mel Wilcox, MD 2 University of Virginia, Charlottesville, VA; 2University of Alabama, GI Division, Birmingham, AL 1

Abstract: Aspirin, used at low doses (75–325 mg daily), prevents aggregation of platelets and is prescribed for patients as pharmacologic prevention of cardiovascular disease. Despite the well-documented beneficial effects of aspirin, prolonged use is associated with damage to the gastrointestinal (GI) mucosa in the upper and lower GI tract. Patient risk of hemorrhage and peptic ulcer formation is increased with older age, previous ulcer history, Helicobacter pylori infection, and concomitant use of nonsteroidal anti-inflammatory drugs, corticosteroids, or antithrombotic agents. As termination of aspirin therapy can precipitate a cardiovascular event, patients at risk need co-therapy with gastroprotective agents, such as proton pump inhibitors (PPIs), to reduce the GI side effects of aspirin treatment. Fixed-dose combinations of low-dose aspirin and gastroprotective agents have been designed to increase medication compliance, improve clinical outcomes, and reduce the overall cost of therapy. Prolonged use of PPIs may, however, lead to serious adverse effects or, in some cases, reduce the cardioprotective effects of aspirin. Hence, physicians need to carefully consider the benefits and risks associated with the condition of each patient to optimize clinical outcomes of combination therapy. A growing body of clinical evidence indicates that aspirin may decrease the risk of colorectal and other GI cancers, as well as reduce progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma. Furthermore, PPIs have recently been shown to reduce neoplastic transformation in patients with BE. Thus, the use of a fixed-dose aspirin/PPI combination could potentially provide chemopreventive benefit to patients with BE, and, at the same time, treat the underlying gastroesophageal reflux responsible for the condition. Keywords: aspirin; fixed-dose combination; proton pump inhibitors; cardiovascular disease; Barrett’s esophagus

Introduction

Correspondence: David A. Peura, MD, PO Box 800708 HSC, University of Virginia, Charlottesville, VA 22908–0708. Tel: 434-924-0316 Fax: 434-924-0491 E-mail: [email protected]

Aspirin treatment helps prevent the development and progression of many comorbid conditions in patients, such as cardiovascular disease (CVD), esophageal adenocarcinoma in the setting of Barrett’s esophagus (BE), and various gastrointestinal (GI) cancers.1,2 Despite its widespread beneficial effects, aspirin, even at low doses, increases risk for GI ulceration and bleeding3–5 and up to 20% of low-dose aspirin (LDA) users report dyspeptic symptoms.6 Thus, taking into account the beneficial role of aspirin, there is a need for gastroprotective therapies, especially in patients at risk for cardiovascular complications or GI cancer, who depend on continuous aspirin therapy. To reduce the risk of aspirin-related upper-GI side effects, a variety of strategies have been developed, including oral prostaglandin analogs, H2 receptor antagonists (H2RAs), and proton pump inhibitors (PPIs).7 Use of PPI therapy is currently considered

© Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 87 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


David A. Peura and C. Mel Wilcox

the most effective method of gastroprotection.7 Low-dose aspirin, administered along with a gastroprotective agent, has proven safe and effective in preventing gastric mucosal injury in patients.8–14 Fixed-dose combinations (FDCs), which are formulations including $ 2 active therapeutics combined in a single dosage form, have been designed to improve patient compliance with the medication regimen and to increase cost-effectiveness of the prescribed therapy.15,16 We discuss the benefits and challenges of co-therapy and FDC therapies that provide both the cardioprotective effects of LDA and gastroprotection. We also present evidence of the chemopreventive effects of therapy with aspirin alone or in combination with PPIs in patients with BE and various cancers of the digestive tract.

Role of Aspirin in Prevention of CVD

Cardiovascular disease is the leading cause of mortality in the US population.17 Preventive care and lifestyle modifications that address risk factors such as tobacco use, obesity, lack of exercise, hypertension, diabetes, and dyslipidemia can be used to reduce the incidence of atherosclerotic CVD. Pharmacologic intervention, such as LDA (75–325 mg daily), is increasingly being used for primary and secondary prevention of CVD,18–20 including myocardial infarction (MI) and stroke.21,22 Results from a meta-analysis of 12 randomized clinical trials of aspirin use in patients with a history of MI showed that long-term LDA therapy, via inhibition of platelet aggregation, reduced the relative risk of nonfatal MI by 28% (P , 0.0001), vascular death by 15% (P , 0.0006), and overall mortality by 11% (P = 0.02).1 Activation of platelets and subsequent induction of the clotting cascade lead to platelet aggregation and contribute to the occurrence of acute occlusive cardiovascular events.23 Aspirin’s role in cardiovascular protection relies on inhibition of platelet activation and aggregation.24 Specifically, aspirin irreversibly inhibits platelet-dependent enzyme cyclooxygenases, COX-1 and COX-2, thereby preventing synthesis of prostaglandins and thromboxane A2, which normally promote platelet aggregation.25,26

Chemopreventive Role of Aspirin in BE, Colorectal, and Other Gastric Cancers

Although the incidence of esophageal adenocarcinoma in the United States increased 6-fold between 1973 and 2001, incidence of the early disease stage plateaued in 1999, and did not increase through 2006.27 Several possible explanations for this phenomenon have been suggested, including 88

decreased exposure to initiating factors, slower transition from premalignant BE to cancer, and increased exposure to protective factors.27 Clinical studies have reported that use of over-the counter (OTC) aspirin has been associated with a 30% to 60% decreased patient risk of developing BE, esophageal, and gastric cancers,28 and have shown a trend towards reduced patient risk of transition from BE to n eoplasia.29 A recent meta-analysis of all observational studies conducted before 2011 on the chemopreventive efficacy of aspirin in colorectal, gastric, and esophageal cancers confirmed the antineoplastic effect of aspirin.30 Furthermore, a metaanalysis of all randomized, placebo-controlled trials that evaluated aspirin for the prevention of colorectal adenomas showed that LDA (81–325 mg daily) was effective in patients with a previous history of these lesions.31 The chemopreventive mechanism of aspirin has been attributed to inhibition of the COX-1 and 2 enzymes, which are abnormally expressed in many cancer cell lines, and regulating production of prostaglandin 2 (PGE2), which promotes resistance to apoptosis, increases angiogenesis, and enhances cell invasion.30,32,33 Furthermore, it has been hypothesized that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the acquisition rate of somatic genomic abnormalities in BE and thereby inhibit progression to esophageal adenocarcinoma.34

Aspirin-Induced GI Injury

Aspirin-induced GI damage is caused by both epithelial and microvascular effects (with minimal or no inflammation).35 Aspirin inhibits COX-1 expression, thereby depleting prostaglandins, resulting in GI mucosal and systemic events36–38; clinical significance resides in the pivotal role of prostaglandins in protecting gastric mucosal integrity by increasing local blood flow and promoting synthesis and secretion of mucus and bicarbonate. The topical effects on the gastric mucosa can be visualized via endoscopy within minutes of aspirin administration.39 Additionally, LDA promotes GI bleeding through its antiplatelet effect38; however, the predominance of local or systemic events in aspirin-related GI injury continues to be examined.40 Conventional patient risk factors for upper GI complications associated with aspirin therapy include a history of peptic ulcer disease/GI bleeding, being aged $ 60 years, concomitant use of other NSAIDs (often purchased OTC and used without a health care practitioner’s knowledge or approval), anticoagulants, or other antiplatelet medications,41 the presence of severe comorbidities, and high aspirin dose.3 Based on information from clinical studies, reported incidence of gastric ulcers

© Postgraduate Medicine, Volume 126, Issue 1, January 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Fixed-Dose Combination of Aspirin and Proton Pump Inhibitors


or gastric erosions caused by aspirin use varies widely, depending on the endpoint measured, demographic characteristics of the study population, as well as the dose and length of aspirin treatment. According to a study by Yeomans et al,6 incidence of gastroduodenal ulcers in patients with CVD taking LDA for 3 months was 7%. In patients at high risk for aspirin-induced ulcers, incidence of gastroduodenal ulcers was 17.6% after 7 days of LDA administration, and overall occurrence of gastric erosions or ulcers approached 42.2%.40 The definite and probable predictors of aspirinrelated upper GI bleeding identified in clinical studies are summarized in Table 1.

Methods of Preventing AspirinInduced GI Injury

Several methods to prevent aspirin-induced GI injury are used in clinical practice, including Helicobacter pylori eradication, enteric-coated or buffered LDA administration (although this may not mitigate the risk of systemic effects on the GI tract), and co-administration of various gastroprotective therapeutics.7,42 Use of H2RAs is reported to suppress gastric acid production by 37% to 68% over 24 hours and to have a modest protective effect in patients taking aspirin43; they are more effective than placebo in decreasing risk of gastric and duodenal ulcers,13 but not as effective as PPIs.11,43 Efficacy of misoprostol is comparable to a PPI, but misoprostol requires multiple daily dosing and is not as well tolerated; the most common adverse effects include abdominal pain and dose-related diarrhea.44 For these reasons, misoprostol is prescribed less frequently than PPIs.45 Proton pump inhibitors are the preferred therapy for preventing aspirin-induced GI injury, especially in patients who are at-risk LDA users.3,7 Gastroprotection with PPI use is achieved by raising intragastric pH,46 which decreases the risk of GI ulceration and associated complications.47–52 The most common upper GI gastroprotective strategies used in clinical practice are summarized in Table 2.

Benefits of Combination Therapy in CVD

The efficacy and safety of gastroprotective co-therapy and FDCs have been well established (Table 3).8–14 In the ASTERIX and OBERON studies, an FDC regimen of aspirin and a PPI (esomeprazole) resulted in reduced incidence of peptic ulcers and dyspeptic symptoms compared with aspirin plus placebo.12,14,53 Furthermore, despite early termination of the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT), prophylactic use of a PPI in patients receiving aspirin and clopidogrel reduced the rate of upper GI bleeding.8

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is among the most effective treatments for patients after acute coronary syndromes.54 Patients on DAPT often are co-prescribed PPIs, with the exception of omeprazole and esomeprazole, due to possible drug–drug interactions with clopidogrel.54Co-administration of an NSAID, such as naproxen, diclofenac, or ibuprofen, with a PPI and aspirin is acceptable, if needed.55 A phase 1 clinical study was initiated to evaluate the therapeutic efficacy, measured by the time that intragastric pH was maintained, of esomeprazole and LDA combined in a single capsule (20 mg esomeprazole, 81 mg aspirin) compared with the same 2 medications taken separately, but the study was terminated and the results have not yet been reported (ClinicalTrials.gov Identifier #NCT01015729). A recent pharmacokinetic study has demonstrated that an aspirin/esomeprazole FDC (40 mg esomeprazole, 325 mg aspirin) is bioequivalent to the individual medications. The mean geometric ratios for maximum plasma concentrations for single-capsule formulation compared with use of the individual agents taken at the same time were 0.99 (94% CI, 0.90–1.09) and 1.02 (94% CI, 0.92–1.13; 1.00–1.08), respectively.56 Fixed-dose combinations may provide a viable Table 1. Predictors of Aspirin-Related Upper GI Bleeding Patient Risk Factors

Riska Definite Probable Controversial

Previous history of peptic ulcers or GI bleeding Concomitant use with NSAIDs Helicobacter pylori infection Oversensitivity to aspirin resulting in GI bleeding within the first month of use Concomitant use with anticoagulants Concomitant use with corticosteroids Alcohol abuse Overweight History of dyspepsia High aspirin dose Regular use of aspirin Older age ($ 60 years) Presence of serious comorbid conditions

+ + + +

+ + + + + + + + +

Risk classified as: Definite, based on consistent and reproducible data from clinical trials; Probable, based on variable and inconsistent data from clinical trials; Controversial, no statistically significant data available. Abbreviations: GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs. Adapted from Valkhoff VE, Sturkenboom MC, Kuipers EJ. Risk factors for gastrointestinal bleeding associated with low-dose aspirin. Best Pract Res Clin Gastroenterol. 2012;26(2):125–140.3 a



Table 2. Gastroprotective Strategies Used to Reduce Aspirin-Related Upper GI Injury3,7,86,87 Strategy

Mechanism of Action

Challenges

Reduced use of aspirin with other NSAIDs, corticosteroids, and anticoagulants

Adverse events on upper GI tract are potentiated with the use of concomitant medications

Not always feasible

Reduced aspirin dose (75–81 mg/day)

Reduced dose is less efficient in inhibiting platelet aggregation

Diminished cardiovascular protection

Treatment of Helicobacter pylori infection

Decreased occurrence of upper GI injury after eradication of the bacteria

Treatment with antibiotics

Misoprostol, synthetic prostaglandin

Replaces prostaglandin, reduces formation of ulcers

Rarely used due to side effects such as diarrhea and abdominal cramping

H2RA: ranitidine, famotidine

Increase gastric pH, reduce gastric acid production

Twice daily dosing and relatively low efficacy

Parietal cell PPI: dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rebeprazole

Suppress gastric acid production

Should be administered 30 min before food consumption to ensure maximal efficacy Risk for fractures with prolonged therapy


Co-therapy with a gastroprotective agent:

Abbreviations: GI, gastrointestinal; H2RA, H2 receptor agonist; NSAIDs, nonsteroidal anti-inflammatory drug; PPI, protein pump inhibitor.

option for the management of certain chronic diseases (eg, CVD), as the risk of noncompliance to the medication regimen is reduced by approximately 25% compared with medications dosed individually.15 Thus, an aspirin/PPI combination offers a more convenient dosing regimen than the traditional approach (2 separate medications) and may improve patient compliance.57 Use of FDCs would also benefit patients without GI symptoms who would not otherwise be prescribed a PPI. Evidence for this comes from studies demonstrating that gastroduodenal ulcers may occur in up to 50% of asymptomatic patients who receive long-term treatment with LDA.6,58 The risk factors noted in Table 1 associated with GI events in conjunction with a prescribed LDA regimen may justify the need for prophylactic FDC with aspirin and PPI, even in asymptomatic patients. A cost-effective benefit should also be realized when an FDC regimen is used, with single-pill CVD prophylaxis leading to patient cost savings from fewer physician/health care visits, less laboratory work, and reduced medical testing due to dyspepsia and bleeding. However, based on cost-utility and cost-effectiveness studies, combination therapy may not always be cost-effective. A recent study examined use of aspirin, with and without the addition of a PPI, in men with CVD who were at risk for GI bleeding and found that combination therapy provided more quality-adjusted life years but also incurred higher costs (US $21 037) compared to aspirin monotherapy (US $17 571). The combination therapy became cost-effective in men with highly increased risk for GI bleeding (7 in 1000 patients).59 Another study evaluated the 90

benefit of combination therapy for patients taking LDA for secondary CVD prevention. The average age of participants was 65 years, with the average bleeding risk of 2.5 in 1000 patients. Study results showed that co-administration of a PPI was cost-effective in this patient population, but not in younger patients.60 The annual per-patient cost of generic OTC PPI therapy in the United States, estimated in 2007, was US $250,60 and the average annual LDA therapy cost, estimated in 2002, was $172 and varied between $50 and $200, depending on the cost of management of aspirin-related complications.61 The cost-effectiveness of aspirin/PPI FDC remains to be determined, and will depend on pricing and insurance coverage for the drug. According to a study by Zhu et al, conducted in China, only 3.46% of prescription aspirin users also received gastroprotective medications, such as PPIs and H2RAs, revealing poor awareness of the need for combined protective medications to prevent aspirin-induced GI injury in patients.62 Results from a recent study conducted in the Netherlands showed that in patients who were at increased risk of GI complications, concomitant regular use of PPIs reached 46%. A large proportion of patients (36%) did not receive PPI prescriptions, and 18% obtained prescriptions irregularly, indicating that primary care physicians did not always prescribe combination therapy for aspirin users with increased risk for GI complications.63 As most LDA and some PPIs can be obtained OTC in the United States, it is difficult to accurately track co-administration and the US physicians’ awareness of aspirin-associated GI injury. An FDC would help to track frequency of co-administration, which




Table 3. Efficacy and Safety of Combination LDA/Gastroprotective Agent or FDC Therapy in Reducing Gastric Ulcers/Erosions in Patients at Increased Cardiovascular Risk Combination vs Control Treatment (mg/d)

n (per arm) Percent of Patients Developing Gastric Ulcers

P Value Most Common AEs (Combination % LDA + GPA LDA + Control vs Control %)

RCT –Duration –Type

LDA/esomeprazole (20) vs LDA/placebo

493 498

1.8

ASTERIX14 Yeomans et al14 – 26 weeks – Placebo-controlled, endoscopic

LDA/esomeprazole (40) and LDA/esomeprazole (20) vs LDA/placebo

817 804 805

1.5 1.1

LDA/lansoprazole (60) vs LDA/placebo

62 61

1.6a

0.0007 6.2

0.0001 7.4

Heartburn: 89.7 vs 66.7 Acid regurgitation: 86.4 vs 56.5 Epigastric pain: 72.7 vs 58.1 Nausea 1.8 and 0.8 vs 0.7 Diarrhea 2.6 and 3.4 vs 2.2

0.008

None reported

0.001

Diarrhea 3 vs 1.8

0.0002

None reported

NR

None reported

0.03

Dyspepsia 0 vs 12.3

14.8a

LDA/clopidogrel/omeprazole (75/20)b vs 1876 LDA/clopidogrel (75)/placebo 1885

1.1c

LDA/famotidine (40) LDA/placebo

204 200

3.4

LDA/misoprostol (0.1) LDA/placebo

16 16

17d

LDA/pantoprazole (20) LDA/famotidine (80)

65 65

0d

2.9c

15

52d

7.7–12.3e

OBERON12 Scheiman et al12 – 26 weeks – Placebo-controlled, endoscopic Lai et al10 – 12 months – Placebo-controlled, endoscopic – All patients had H. pylori infection COGENT8 Bhatt et al8 – 180 days – Placebo-controlled FAMOUS13 Taha et al13 – 12 weeks – Placebo-controlled Donnelly et al9 – 28 days – Placebo-controlled, endoscopic – All participants were healthy and had no ulcers Ng et al11 – 48 weeks – Placebo-controlled

Percent of patients with recurrent ulcers. FDC of clopidrogel/omeprazole; LDA, 75–300 mg/d. c Composite incidence of bleeding, symptomatic gastroduodenal ulcers, or erosions. d Percent of patients with $ 1 gastric erosion (not ulcers). e Percent of patients with recurrent dyspeptic or bleeding ulcers/erosions within 48 weeks. Abbreviations: AE, adverse events; FDC, fixed-dose combination; GPA, gastroprotective agent; LDA, low-dose aspirin; NR, not reported; RCT, randomized controlled trial. a

b

would help to better define the need for combined protective medications, and improve compliance among US patients. Future cost-effectiveness and modeling studies would also facilitate a more thorough assessment of the benefits and challenges associated with the use of FDC regimens.

Benefits of Aspirin and PPIs in Preventing BE, Colorectal, and Other Gastric Cancers

As noted, aspirin therapy has been shown to have chemopreventive and antineoplastic properties for a variety of GI

cancers.30 Routine administration of aspirin to alter the natural history of premalignant GI conditions remains controversial because controlled data confirming efficacy is lacking, and aspirin use can lead to GI complications. Esophageal exposure to acid is an important factor in the pathogenesis of BE, and possibly, progression of BE to esophageal adenocarcinoma. Acid suppressants, such as PPIs, are frequently used to treat patients with BE, but it has been unclear whether PPIs can also prevent the development of BE-related neoplasms. Several clinical studies have reported that therapy with PPIs after BE diagnosis was


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associated with significantly reduced risk of BE progression to high-grade dysplasia or cancer (Table 4).29,64,65 In a multicenter p rospective cohort study of 540 patients with BE, acid suppression with PPIs significantly reduced the risk of neoplastic progression (P = 0.002), and this effect was even more pronounced with long-term PPI use.66 Combination therapy of aspirin and PPI has recently been tested in patients with BE. In a randomized, double-blind, placebo-controlled, phase 2 study, the effects of the combination of esomeprazole and 3 different doses of aspirin on tissue concentrations of PGE2, a plausible biomarker of increased risk of GI cancers, were assessed in patients with BE with no or low-grade dysplasia. Based on results from 114 patients, higher doses of aspirin in combination with esomeprazole led to significant reduction in tissue concentrations of PGE2 (Table 4).33 The therapeutic effect of co-administration of

aspirin and PPI in patients with long-segment Barrett’s metaplasia of the esophagus is currently being addressed in an ongoing, large, randomized, controlled, phase 3, 8-yearfollow-up trial funded by external grant authorities in the United Kingdom. The Aspirin Esomeprazole Chemoprevention Trial (AspECT; EudraCT number: 2004–003836–77) has been designed to test a high dose (80 mg) and a low dose (20 mg) of esomeprazole with either LDA (300 mg) or no aspirin.32,33,67 The study is in the follow-up phase, with estimated study completion in 2019. In light of previous findings, an aspirin/PPI combination could potentially be an attractive therapeutic option for patients with BE. Effectively treating acid reflux as well as preventing neoplastic transition from BE to esophageal adenocarcinoma could reduce the need for endoscopic mucosal resection, surgical resection, or ablation therapies.68

Table 4. Efficacy of PPI Therapy Alone or in Combination With Aspirin in Reducing High-Grade Dysplasia/Cancer in Patients With BE Therapy

Comparator

Risk of High-Grade Dysplasia or Cancer Hazard Ratio Therapy/ Comparator

95% CI

P Value

% Risk Reduction on PPI Treatment

RCT –Duration –Type

Nguyen et al29 – 5.1 years follow-up – Observational, retrospective, endoscopic, patients with BE El Serag et al65 – 1.170 patient years – Observational, prospective, endoscopic, patients with BE Hillman et al66 – Median follow up 4.7 years – Observational, prospective, endoscopic, patients with BE Kastelein et al67 – Median follow up 5.2 years – Multicenter prospective cohort study, endoscopic patients with BE

PPI n = 231

No PPI (NSAID/Aspirin or Statin) n = 256

0.43

0.21–0.83

NR

75

No PPI (either H2RA or no therapy) n = 83

0.25

0.13–0.47

0.0001

61

PPI n = 462

No PPI 5.64a (delayed PPI use for $ 2 years) n = 55

2.02–15.7

0.001

NR

PPI n = 532

Noneb

0.07–0.66

NR

NR

Aspirin low dose/PPI n = 43 Aspirin high dose/PPI n = 42

Placebo/PPI n = 29

0.21c

Absolute Change in PGE2 Levels Compared With Placebo Mean (SD)

P Value Compared With Placebo

-123.9 (284.0)

P = 0.09

-174.9 (263.62)

P = 0.02

Falk et al33 – 28 days – Randomized, placebocontrolled, patients with BE

Risk of low-grade dysplasia. No comparator; time-dependent Cox regression models were used. Risk of neoplastic progression. Abbreviations: BE, Barrett’s esophagus; NR, not reported; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor. a

b c

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Challenges Associated With Prolonged PPI Therapy

In addition to the benefits of combination therapies, there are several inherent challenges that will need to be addressed through both retrospective and prospective clinical analyses and cost-effective modeling studies. Potential disadvantages of the use of PPIs include the occurrence of side effects, the lack of protective effect on aspirin-associated injury in the lower GI tract, and the requirement of meal time administration (PPIs should be administered 30 minutes before a meal to achieve maximum efficacy).7 The most common adverse events associated with PPI therapy are epigastric pain/discomfort, heartburn, nausea, headache, diarrhea, and bloating (Table 3).8,12,14 Several recently published meta-analyses have pointed out a possible association between the use of PPIs and the incidence of Clostridium difficile infection (CDI).69–71 The proposed explanation of the phenomenon is that a less acidic gastric environment, suppressed by PPI, may lead to increased bacterial colonization of the upper GI tract.71 Furthermore, PPI-treated patients taking broad-spectrum antibiotics for underlying medical conditions can occasionally develop C. difficile–associated diarrhea. Based on these findings, the US Food and Drug Administration (FDA) issued a warning regarding increased risk of CDI among patients taking long-term PPIs.72 Other studies, however, failed to find sufficient evidence for a causal relationship between the use of PPIs and occurrence of CDI.73 Routine PPI administration over a prolonged period of time has recently been shown to increase the risk of fractures of the hip, wrist, and spine in patients aged $ 50 years.74 Patients treated with PPIs for . 1 year may have lower magnesium levels.75 Additionally, certain PPIs, such as omeprazole and esomeprazole, demonstrate unfavorable drug–drug interactions with clopidigrel and have the potential to cause adverse cardiovascular events. Omeprazole and esomeprazole may inhibit the CYP2C19 enzyme responsible for the conversion of clopidogrel into its active form, and thereby reduce its antiplatelet effect76; however, the clopidrogel–PPI interaction and its impact on cardiovascular risk has to be conclusively proven in well-controlled, randomized clinical studies.43 Additionally, a recent, retrospective, nationwide clinical study suggested that use of PPIs in aspirin-treated patients with first-time MI may be associated with an increased risk of a combined endpoint of cardiovascular death, MI, or stroke, which have not been observed in patients treated with other gastroprotective agents.77 As well as inducing bleeding and ulceration of the upper GI tract, prolonged LDA therapy may cause small bowel and

colon injury. The PPIs exert no protective effect on this part of the GI tract and no other strategy to reduce this potential problem is currently available.7

Adherence to Aspirin Monotherapy Compared With Aspirin/PPI Combination Therapy

In a study assessing self-reported patient adherence during a 12-month treatment course, 70% of subjects were adherent to aspirin therapy and only 45% of patients analyzed were adherent to lipid- and blood-pressure-lowering therapy.78 Suboptimal medication adherence can increase the gap between implementation of clinical practice guidelines and expected outcomes (ie, patient improvements).79 The number of pills taken daily is inversely correlated with adherence to a medication regimen.80 Patients who are prescribed LDA therapy and are at risk of GI complications may fail to take a PPI as part of the regimen, especially if they are taking multiple other medications.63 This becomes increasingly important when LDA therapy is recommended for longer-term use; the GI side effects of LDA use without a PPI in this scenario include ulcerations and upper GI bleeding. Though PPIs are known to reduce gastric symptoms, patient adherence to an aspirin and PPI co-therapy regimen for gastroprotection remains poor.40

Current Status of FDC Aspirin Therapy and Future Direction

Recently, increasing interest has focused on whether coadministration of PPIs and aspirin can potentially attenuate the antiplatelet effect and cardiovascular benefit of aspirin.8 The hypothesis is based on the assumption that changing the intragastric pH may affect absorption of aspirin across the gastric mucosal membrane and thereby diminish its bioavailability.46 However, current clinical evidence of drug interactions between aspirin and PPIs is rather inconclusive and contradictory, stressing the importance of further investigation.46 Several therapeutics combining NSAIDs and gastroprotective agents have already been approved in the United States, including diclofenac and misoprostol, naproxen and esomeprazole, and ibuprofen and famotidine.81 Each of the combination products has been shown to diminish harmful GI effects of the NSAID component and their clinical use is expected to improve adherence.81 Based on the results from the ASTERIX and OBERON clinical trials, an FDC of LDA and esomeprazole82 was approved in 2011 in 23 European countries for use as a once-daily regimen for the prevention


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of cardiovascular and cerebrovascular events46,83,84; however, the formulation has not been approved by the FDA for use in the United States, due to possible increased side effects associated with prolonged use of PPIs.85


Summary

Prolonged aspirin use damages the gastric epithelium, which may lead to ulcerations and GI bleeding. Gastroprotective strategies to reduce the risk of GI injury include the use of H2RAs and PPIs, which reduce stomach acid production and allow gastric ulcers and erosions to heal. Clinical trials have shown that PPIs are relatively well tolerated and associated with a significant reduction in the risk of GI bleeding and ulcers. The PPIs have superior efficacy compared with H2RAs and cause fewer adverse events than prostaglandinreplacement therapy. There are, currently, no definitive data supporting the notion of an aspirin—PPI interaction, but several adverse effects of prolonged PPI use have been described. Thus far, the aspirin/PPI combination has been proven effective in preventing CVD and has shown antineoplastic effects in patients with BE. If supported by positive results from clinical studies, aspirin/PPI combinations could also be the future treatment of choice for patients with colorectal and other GI cancers who experience or are at risk of GI side effects from prolonged aspirin use. Fixed-dose combinations of LDA/PPI may improve medication compliance, which can potentially translate into beneficial clinical outcomes and reduced overall cost of therapy. More largescale, long-term clinical studies are needed to conclusively assess the efficacy and safety of aspirin/PPI combinations and FDC therapy in patients with CVD or with GI neoplasms.

Acknowledgments

Editorial support was provided by Courtney MezzacappaZeni, PhD, and Ewa Wandzioch, PhD, from QSci Communications, with funding from Pozen.

Conflict of Interest Statement

David A. Peura, MD, has served as a consultant for AstraZeneca and Pfizer; as a consultant and speaker for Takeda Pharmaceuticals North America, Inc; and a speaker for Horizon Pharma. C. Mel Wilcox, MD, discloses no conflicts of interest.

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Aspirin for primary prevention of cardiovascular disease.

Low adherence to national guidelines for proton-pump inhibitor prescription in patients receiving combination aspirin and anticoagulation.

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Fixed-dose combination therapy for the prevention of cardiovascular disease.

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Aspirin overutilization for the primary prevention of cardiovascular disease.

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Treatment and prevention of cardiovascular disease by aspirin.

Proton pump inhibitor-associated hypomagnesaemia and hypocalcaemia.

Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy.

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Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries.

Effect of low-dose proton pump inhibitor on preventing upper gastrointestinal bleeding in chronic kidney disease patients receiving aspirin.

Aspirin for Primary Prevention of Cardiovascular Disease and Cancer. A Benefit and Harm Analysis.

Combination therapy of gamma-aminobutyric acid derivative promotes proton pump inhibitor based healing of reflux esophagitis in animal model.

Medical Prevention of Barrett's Esophagus: Effects of Statins, Aspirin, Non-aspirin NSAIDs, Calcium, and Multivitamins.

[Primary cardiovascular prevention with aspirin].

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