Prevalence and Associated Clinical Factors of GERD (Gastro-Esophageal Reflux Disease) in Ischemic Stroke Patients

Gastro-esophageal reflux disease (GERD) is defined as the condition that develops when the reflux of stomach contents causes troublesome symptoms or complications, including reflux esophagitis (RE) [1], and is common in daily clinical practice [2]. Although aspirin is frequently used as an antiplatelet agent in patients with ischemic stroke [3], owing to its ability to reduce overall stroke rates in secondary stroke prevention [4], it has recently been considered a risk factor for GERD symptoms [5,6].


Introduction
Gastro-esophageal reflux disease (GERD) is defined as the condition that develops when the reflux of stomach contents causes troublesome symptoms or complications, including reflux esophagitis (RE) [1], and is common in daily clinical practice [2]. Although aspirin is frequently used as an antiplatelet agent in patients with ischemic stroke [3], owing to its ability to reduce overall stroke rates in secondary stroke prevention [4], it has recently been considered a risk factor for GERD symptoms [5,6].
The association between aspirin and GERD is well established, but few studies have examined the relationship between oral aspirin and GERD in ischemic stroke patients.
Here, we investigated the prevalence and associated clinical factors of GERD in patients with ischemic stroke patients treated with aspirin.

Methods
The subjects were ischemic stroke patients who had been treated in the outpatient clinic of the Ryotenkai Katagi Neurosurgery in April and May 2012. Enrollment was limited to ischemic stroke patients aged > 20 years from whom written informed consent was obtained. All study patients underwent antithrombotic low-dose aspirin therapy (81-100mg /day) and gastric coating agents. Patients who had received proton pump inhibitors or H2 receptor antagonists within 1 month or who had life-threatening complications were excluded. Patients were met prior to GerdQ questionnaire by the researcher to discuss the study, obtain informed consent from patients willing to take part, and scheduled an interview. The study was conducted in accordance with the principles of the Declaration of Helsinki.

GerdQ questionnaire
GerdQ is a well-documented questionnaire which was developed under a rigorous evidence-based approach [7,8]. In one study, patients with a GerdQ score of 8 or higher were regarded as having GERD, and a clinical approach based on this classification was shown to provide lower health care costs than an empirical approach without any loss of efficacy [9]. Following these findings, GerdQ is now considered a useful tool for the diagnosis of GERD without the need for specialist referral or endoscopy (gastroenterological evaluation).
3) dyspepsia, 4) nausea, 5) sleep disturbance, and 6) need for over-thecounter (OTC) treatment during the past 7 days using a 4-point scale with a score range of 0 to 3 (0=0 days/week; 1=1 day/week; 2=2-3 days/ week; and 3=4-7 days/week). In accordance with previous reports, patients with a GerdQ score of 8 or higher of a maximum possible score of 18 were regarded as having GERD (7-9). Endoscopy was not performed. Medical records and drug history were retrospectively surveyed to clarify factors involved in GERD.

Statistical analysis
Continuous values were expressed as the mean ± SD. Subjects were divided into two groups using a GerdQ score of 8 points as cut-off. The significance of differences in mean values and proportions was tested using Student's t-test for continuous variables and the chi-squared test for dichotomous variables. This was followed by a multivariable logistic regression analysis including those variables with a p < 0.1 in the univariate analysis. A two-tailed P value of <0.05 was regarded as significant. For analysis, we employed SPSS version 13.0 (SPSS Inc., Chicago, IL).

Results
A total of 100 patients were analyzed (Table 2). Mean patient age was 69.3 ± 8.9 years, and 59% (59) were male. Twenty-eight patients (28%) had GERD (GerdQ score ≥ 8). Clinical details of patients with and without GERD are compared in Table 2. Mean BW of patients with GERD was significantly higher than of those without GERD (P= 0.02). The proportion of patients receiving ARBs (46% vs. 69%; P=0.04) was significantly lower in the GERD group. In contrast, no significant difference was seen in the proportion of patients receiving CCBs (68% vs. 75%; P=0.47), while the proportion prescribed lipid lowering agents or oral glucose-lowering agents in the two groups was similar.
Multivariable logistic regression analysis was done using GERDassociated variables which had been found significant or marginally significant in the previous analysis (Table 2), with the presence or absence of GERD as the dependent variable. Results showed that BW (odds ratio (OR) 1.086; 95% confidence interval (CI): 1.020-1.157; P < 0.05) and ARB use (OR 0.302; 95% CI: 0. 112-0. 819; P < 0.05) were associated with the presence of GERD. SBP and diuretics uses were not significantly associated (Table 3).

Discussion
In this study, the prevalence of GERD in patients with ischemic   stroke as identified using the GerdQ questionnaire was 28%, which is higher than the approximately 10-20% prevalence previously reported in the general population [2,10]. This increase can be ascribed to the use of antiplatelet agents in these patients despite use of gastric coating agents. Ercelep et al. demonstrated that antiplatelet therapy was an independent risk factor for GERD symptoms [11]. Moreover, 16 patients were excluded from the present study owing to their use of proton pump inhibitors or H2 receptor antagonists for GERD symptoms within the previous month; inclusion of these patients would have increase the prevalence of GERD to approximately 38%. These findings highlight the need to protect patients with ischemic stroke from the development of GERD.
Our finding that BW was positively associated with the presence of GERD is consistent with a previous finding of a significant association with a body mass index (BMI) over 30 [11]. Recently, Niigaki et al. demonstrated that metabolic syndrome, a cluster of metabolic risk factors, was a significant predictive factor for the prevalence of GERD [12]. In contrast to our findings, however, they also found that subjects undergoing treatment for dyslipidemia and diabetes mellitus were at decreased risk of GERD. One reason for this difference might be the relatively young age of their participants, with a mean of 52 years versus our present subjects, at 69 years.
Hypertension is the single most important modifiable risk factor for recurrent stroke. Although blood pressure control is an important intervention for secondary stroke prevention [13], subjects undergoing treatment for hypertension are at increased risk of GERD [14]. The selection of antihypertensive drugs therefore requires consideration of digestive system function. In our subjects, use of either ARB or CCB was high, at 63% and 73%, respectively, while 52% received combination therapy. Among antihypertensive drugs, ARBs are considered to have greater efficacy in stroke prevention that CCB [15]. Generally, agents that relax the lower esophageal sphincter (LES) can induce GERD symptoms; CCBs in particular may decrease LES pressure and lead to the onset of GERD. In this regard, Horikawa et al. found that the prevalence of GERD was correlated with the proportion of patients treated with CCB on univariate correlation analysis, but found no significant association on logistic regression analysis, as in the present study [14].
The most intriguing result of our study was that the antihypertensive agent ARB was negatively associated with the presence of GERD. Multiple logistic regression analysis revealed that the combination of ARBs had a significant positive impact on endoscopic healing (OR 3.9, 95% CI 1.411-10.903), whereas no significant positive relationship was seen for other antihypertensive drugs such as CCBs.
Consistent with this finding, Miwa investigated endoscopic findings before and after treatment in 454 RE patients who received PPI therapy for 8 weeks and demonstrated that concomitant use of ARBs promoted endoscopic healing of RE in these patients [16]. Recently, Brzozowski et al. reported a novel concept in the mechanism of protection of gastric mucosa by ARB [17]. They demonstrated a gastro-protective role of angiotensin-(1-7), an ANG II metabolite produced in the breakdown of ARBs. Angiotensin-(1-7) is produced in excessive amounts in the gastric mucosa and exhibits potent gastro-protective activity against gastric lesions. These findings provide evidence to support our results that ARB act as a protector to occurrence of GERD. ARBs appear to be better suited than CCBs for use in patients with ischemic stroke with regard to the prevention of GERD.

Limitations
Several limitations of the study warrant mention. First, sample size was small, which considerably limits the conclusions which can be drawn the data. A large number of prospective studies are required to confirm the result. Second, because there are no reports indicating association between GERD and ARB, it is not clear how ARB might protect the patients from GERD. Third, because the study was conducted under a cross-sectional design, we were unable to analyze the importance of the ARB-induced decrease in GERD. A comprehensive understanding of the relationship between ARBs and GERD prevalence awaits additional studies in a larger number of patients. One of ongoing study would yield some important findings with regard to the prevalence of gastrointestinal complications and related risk factors for low-dose aspirin users [18]. Odds ratio 95% confidence interval Odds ratios adjusted for age and sex. *P<0.05, SBP, systolic blood pressure; ARBs, angiotensin receptor blockers. Table 3: Odds ratios and 95% confidence intervals for independent predictors of GERD, identified by multivariable logistic regression analysis.