**3. Shared risk factors**

The World Health Organization, World Heart Federation [1] and the American Heart Associ‐ ation [3] each agree on a set of risk factors for the development of cardiovascular diseases. These risk factors include smoking, being overweight or obese, living a sedentary lifestyle, and poor diet, as well as having pre-existing diagnoses of high cholesterol, hypertension and diabetes.

In addition to significantly contributing to the risk of developing cardiovascular disease, these same risk factors have also been found in epidemiologic studies to be associated with an increased risk of reporting upper gastrointestinal symptoms. These risk factors are highly prevalent both worldwide and in the United States [1,3].

Below we discuss the mechanism behind, and studies supporting, the association between these risk factors and increased rates of upper gastrointestinal symptoms.

#### **3.1. Current smoking**

inhibitors (although the researchers did not have data medication use to test this hypothesis). Finally, the most recently published study assessed the relationship between atrial fibrillation and gastroesophageal reflux disease in 188 Japanese patients between 28-91 years of age [18]. Patients' gastroesophageal reflux disease status was classified using the F-scale, a question‐ naire specifically designed to screen for gastroesophageal reflux disease. Almost half of

\*Widely used questionnaire in Japan to screen for gastroesophageal reflux disease based upon frequency of 12 common

#Adjusted for age, sex, race, known atherosclerotic risk factors (hypertension, diabetes, hyperlipidemia, and tobacco use) †Adjusted for strong correlates of AF: ischemic heart disease, cardiomyopathy, atrial septal defect, status post coronary

AF= atrial fibrillation; aRR= adjusted relative risk; GERD= gastroesophageal reflux disorder; HR= hazard ratio; PAF=

paroxysmal atrial fibrillation; PPI= proton pump inhibitor; RR= relative risk; USA= United States of America

**Study Description Key Finding**

PPI therapy led to a decrease or disappearance of at least one PAF-related symptom in 14 of 18

GERD associated with increased risk of AF (RR=1.39, 95%CI=1.33-1.45; aRR=1.19,

95%CI=1.13-1.25#; aRR=1.08, 95%CI=1.02-1.13†)

The presence of GERD was associated with a decreased risk of AF (HR=0.81, 95%CI=0.68-0.96) The frequency of symptoms in those with GERD was associated with an increased hazard of AF (p<0.01); with daily symptoms associated with the highest risk (HR=1.30, 95% CI=0.98-1.57; p=0.07)

AF was associated with prevalence of GERD (Fscale score≥8 points) (p<0.001 upon multivariate analysis). The dyspeptic sub-score (2.05±0.29 vs. 0.94±0.12, p =0.018) and the total F-scale score (3.98±0.51 vs. 2.12±0.21, p = 0.019) of AF patients were significantly greater than those in normal

patients.

compared to none.

sinus rhythm.

Endoscopic reports of 640 Austrian patients searched for diagnosis of lone PAF and mention of reflux esophagitis; 18 patients invited to assess the effect of PPI therapy for GERD on paroxysmal AF-related symptoms

Cross-sectional cohort study of adults in the United States Army National Capitol Area Military Healthcare System database; 7,992 patients with diagnosis of AF; 47,845 with

Longitudinal survey study of Olmstead County, Minnesota residents to assess longterm risk of AF with symptomatic GERD; 2,577 (49%) reported GERD; 741 (14%) developed

AF over 11.4 year follow-up period

Cross-sectional survey study of Japanese patients completing screening questionnaire for GERD based upon frequency of 12 common symptoms to evaluate the

relationship between AF and GERD; 46% with

**Table 3.** Relationship Between Atrial Fibrillation and Gastroesophageal-Like Symptoms

diagnosis of GERD

142 Dyspepsia - Advances in Understanding and Management

AF

**Study, year (N=)**

Weigl 2003 (N=18)

Kunz 2009 (N=163,627)

Bunch 2009 (N=5,288)

Shimazu 2011 (N=188)

symptoms

bypass surgery

Over a billion people worldwide are thought to be current smokers. It is estimated that nearly six million people die from tobacco-related deaths annually, and by 2030, this number is projected to surpass 8 million. Smoking is the underlying cause of about 10% of cardiovascular disease [1] and has been consistently found to be a strong and independent risk factor for myocardial infarction and sudden death [2]. Similar findings have been observed with cerebrovascular disease and smoking; with smokers having a 2 to 4 times increased risk of stroke compared with nonsmokers [2]. Consequently, it is not surprising that a large number of studies support the beneficial cardiovascular consequences of smoking cessation [1].

It is theorized that tobacco smoking/use induces upper gastrointestinal symptoms through its effects on the gastric mucosa [19]. The nicotine in tobacco likely causes mucosal injury by augmenting acid and pepsin release, causing duodenogastric reflux and producing free radicals; while at the same time decreasing prostaglandin and mucus production. Addition‐ ally, smoking may reduce lower esophageal sphincter pressure and thus accentuate gastroe‐ sophageal-like dyspeptic symptoms.


\*Rates per the World Heart Federation/World Health Organization [1]

†Rates per the American Heart Association [2]

BMI=body mass index; DASH=Dietary Approaches to Stop Hypertension; DBP=diastolic blood pressure; N/A=not available; SBP=systolic blood pressure

**Table 4.** Worldwide and United States-Specific Prevalence of Risk Factors for Cardiovascular Disease

While not consistently shown in every study [20-22], smoking's correlation with an increased upper gastrointestinal symptom prevalence (compared to abstainers) has been demonstrated to exist in a fair number of observational studies [8,20,23-25].

In an Australian study of 592 survey respondents of which 78 were dyspeptic, smoking was found to significantly increase this risk of reporting dyspeptic symptoms by more than 100% [19]. The Domestic/International Gastroenterology Surveillance Study also demonstrated smoking to be associated with a significantly greater prevalence of upper gastrointestinal symptoms (16% increase in relative risk) compared to those whom abstained from smoking; with the results of multivariate analysis suggesting smoking's largest negative effect was on heartburn and regurgitation (gastroesophageal-like) symptom prevalence [8].

Similar results were observed in two studies of United States veterans. In the first study, tobacco use was found to be associated with more symptoms of dyspepsia (odds ra‐ tio=1.31, 95% confidence interval, 1.03-1.66)[29]. In the second study, a 62% relative in‐ crease in dyspepsia symptom reporting in smokers (41.4%) compared to non-smokers (25.6%) was observed. Again, as in the Domestic/International Gastroenterology Surveil‐ lance Study [8], subanalysis of the latter study suggested tobacco smoking may have a more profound effect on heartburn and regurgitation symptoms, as evidenced by the fact

**Table 5.** Summary of Studies Suggesting an Association Between Smoking and Upper Gastrointestinal Symptoms

**Study Description Key Finding**

Smoking was an independent risk factor for dyspeptic symptoms (OR=2.1,

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145

Prevalence rate of upper gastrointestinal symptoms were 30.8% for smokers and 26.5% for non-smokers, p=0.0003; Upon multivariate regression analysis, p<0.05 only for the relationship between smoking and gastroesophageal-like symptoms (p=0.03) and not ulcer- or dysmotility-like

Tobacco use was significantly associated with dyspeptic symptoms (OR=1.31,

95%CI=1.3-3.6)

Upper Gastrointestinal Symptoms and Cardiovascular Disease

symptoms

95%CI=1.03-1.66)

Multivariate adjusted RR=1.3, 95%CI=0.8-2.1 for current vs. never smokers and OR=1.6, 95% confidence interval, 1.1-2.3 for past vs. never smoker

41.4% of dyspeptics (including those with gastroesophageal-like symptoms) were smokers vs. 25.6% non-dyspeptics; when gastroesophageal-like symptoms were excluded, no significant relationship between dyspeptic symptoms and smoking was seen (p=0.2)

Healthy blood donors in Sydney, Australia completing the Bowel Symptoms Questionnaire; prevalence rate of upper gastrointestinal

Respondents of the Domestic/International Gastroenterology Surveillance Study which surveyed urban, adult populations from 10 countries representing seven geographic areas (Canada, the USA, Switzerland, The Netherlands, Italy, Japan and the Nordic countries) using a study-specific symptom checklist; prevalence rate of upper gastrointestinal symptoms=28%

Respondents completing surveys (modified Bowel Disease Questionnaire) at one of 4 Durham, NC, USA Veterans Administration clinics; prevalence rate of upper gastrointestinal symptoms=30% (general medicine) to 53% (gastroenterology) depending on site of

Cross-sectional survey study of Olmstead County,

Minnesota residents completing the gastroesophageal reflux questionnaire; prevalence rate of frequent upper gastrointestinal symptoms=20%

Employees of the Houston Veterans Affairs Medical Center, Texas, USA, completing the Gastro Esophageal Reflux Questionnaire; prevalence rate of upper gastrointestinal

symptoms=13.2%

recruitment

symptoms=31.4%

CI=confidence interval; OR=odds ratio; RR=relative risk

**Study, Year (N=)**

Nandurkar 1998 (N=592)

Stranghelli 1999 (N=5,581)

Dominitz 1999 (N=1,582)

Locke 1999 (N=1,524)

Shaib 2004 (N=465)


CI=confidence interval; OR=odds ratio; RR=relative risk

While not consistently shown in every study [20-22], smoking's correlation with an increased upper gastrointestinal symptom prevalence (compared to abstainers) has been demonstrated

BMI=body mass index; DASH=Dietary Approaches to Stop Hypertension; DBP=diastolic blood pressure; N/A=not

**Worldwide Prevalence Rate\***

Current smoking 10%-31% 19.0%

(BMI>30 kg/m2) 9.8% (men)/13.8% (women) 34.6%

**United States Prevalence Rate†**

34% 34.6%

31.3% 21.0%

N/A 79.0%

9.7% 13.8%

40% 33%

10% 11.8%

In an Australian study of 592 survey respondents of which 78 were dyspeptic, smoking was found to significantly increase this risk of reporting dyspeptic symptoms by more than 100% [19]. The Domestic/International Gastroenterology Surveillance Study also demonstrated smoking to be associated with a significantly greater prevalence of upper gastrointestinal symptoms (16% increase in relative risk) compared to those whom abstained from smoking; with the results of multivariate analysis suggesting smoking's largest negative effect was on

Similar results were observed in two studies of United States veterans. In the first study, tobacco use was found to be associated with more symptoms of dyspepsia (odds ra‐ tio=1.31, 95% confidence interval, 1.03-1.66)[29]. In the second study, a 62% relative in‐

heartburn and regurgitation (gastroesophageal-like) symptom prevalence [8].

**Table 4.** Worldwide and United States-Specific Prevalence of Risk Factors for Cardiovascular Disease

to exist in a fair number of observational studies [8,20,23-25].

\*Rates per the World Heart Federation/World Health Organization [1]

**Risk Factor**

144 Dyspepsia - Advances in Understanding and Management

Overweight (BMI>25 kg/m2)

activity/week)

Poor diet patterns

High cholesterol

Diabetes

High blood pressure (≥140 SBP/≥90 DBP)

Insufficient physical activity (<150 minutes of moderate physical

(<4 of 5 DASH-diet components)

(Total cholesterol >240 mg/dL)

(Fasting glucose ≥126 mg/dL)

†Rates per the American Heart Association [2]

available; SBP=systolic blood pressure

Obesity

**Table 5.** Summary of Studies Suggesting an Association Between Smoking and Upper Gastrointestinal Symptoms

crease in dyspepsia symptom reporting in smokers (41.4%) compared to non-smokers (25.6%) was observed. Again, as in the Domestic/International Gastroenterology Surveil‐ lance Study [8], subanalysis of the latter study suggested tobacco smoking may have a more profound effect on heartburn and regurgitation symptoms, as evidenced by the fact that the relationship between smoking and upper gastrointestinal symptom prevalence was no longer statistically significant when patients suffering gastroesophageal-like symp‐ toms (~50% of the study population) were excluded from the analysis (p=0.2). This find‐ ing is further supported by a survey study conducted in Olmstead County, Minnesota where residents demonstrating current or past smoking increased respondents' risk of gastroesophageal symptoms by 30-60% [25].

#### **3.2. Overweight or obesity**

Overweight (body mass index ≥25 kg/m<sup>2</sup> ) or obesity (body mass index ≥30 kg/m<sup>2</sup> ) are highly prevalent disorders worldwide and are particular problems in the United States [1,3]. Obesity is strongly related to major cardiovascular risk factors such as elevated blood pressure, glucose intolerance, type 2 diabetes and dyslipidemia. Prospective studies have shown a significant relationship between overweight or obesity and an increased rate of cardiovascular events. In a collaborative meta-analysis of 58 cohorts (221,934 people from 17 countries, 14,297 incident cardiovascular disease outcomes, 1.87 million person-years at risk), patients' risk of coronary heart disease, ischemic stroke and cardiovascular disease were found to increase by 29%, 20% and 23%, respectively, for every 4.56 kg/m<sup>2</sup> increase in body mass index after adjustment for age, gender, and smoking status [26].

The mechanism behind the association between overweight/obesity and increased upper gastrointestinal symptoms is likely multifactorial [22]. First, the poor diet (ie, increased intake of fatty foods) [22] and lack of exercise that leads the overweight/obese state also promotes increased upper gastrointestinal symptoms (see further discussion below). Next, it is possible that abdominal obesity may lead to gastric compression by the surrounding adipose tissue. This causes increased intragastric pressure and relaxation of the lower esophageal sphincter, and ultimately heartburn and regurgitation. Obesity may also lead to the development of hiatal hernia promoting regurgitation symptoms. Lastly, humoral mechanisms related to obesity including increased levels of insulin, leptin, growth factors or hormones may contribute to gastrointestinal symptoms as well [22,27].

**3.3. Insufficient physical activity**

ing upwards with increasing body mass index

UGIS=upper gastrointestinal symptoms

Current guidance [1,29] recommends all adults should do at least 150 minutes a week of moderate-intensity aerobic physical activity, 75 minutes a week of vigorous-intensity aerobic physical activity, or some equivalent combination of both in order to reduce their risk of heart disease and diabetes. In fact, maintaining this level of moderate- or vigorous-intensity physical activity each week has been associated with as much as a 30% decrease in ischemic heart disease risk and a similar reduction (27%) in the risk of developing diabetes. Unfortunately, nearly a third of people worldwide and a fifth of Americans do not meet this goal [1,3]. While the mechanism behind how insufficient physical activity/sedentary lifestyle is associated with upper gastrointestinal symptoms is unclear, it may be that there is a higher rate of overweight/ obesity in those who do not engage in enough physical activity, or the failure of inactive people to obtain the mental (reduced stress, reduced depressive symptoms and increased cognitive

**Figure 2.** Prevalence of Upper Gastrointestinal Symptoms (By Subtype) By Body Mass Index in the Domestic/Interna‐ tional Gastroenterology Surveillance Study [3] Gastroesophogeal-like symptoms are the only symptom subtype trend‐

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147

Limited data evaluating the impact of physical activity on the prevalence of upper gastroin‐ testinal symptoms have been published in the medical literature. In an internet survey of over

function) and bodily health benefits borne from physical activity [29].

Results of the Domestic/International Gastroenterology Surveillance Study [3] suggested that the prevalence of upper gastrointestinal symptom reporting was higher in those with larger body mass indices. However, consistent with the proposed mechanisms listed above, it appeared the majority of the increased symptom burden related to increased body mass was gastroesophageal-like in nature.

In a meta-analysis of 9 studies examining the association between body mass index and gastroesophogeal-like symptoms, six (67%) found a statistically significant association. Furthermore, data from 8 of the 9 studies demonstrated a "dose-response relationship" between body mass index and gastroesophageal symptoms, with an increase in the pooled adjusted odds ratios for symptoms of 1.43 (95% confidence interval, 1.158 to 1.774) for body mass index of 25 kg/m<sup>2</sup> to 30 kg/m<sup>2</sup> and 1.94 (95% confidence interval, 1.468 to 2.566) for body mass index ≥ 30 kg/m<sup>2</sup> [28].

UGIS=upper gastrointestinal symptoms

that the relationship between smoking and upper gastrointestinal symptom prevalence was no longer statistically significant when patients suffering gastroesophageal-like symp‐ toms (~50% of the study population) were excluded from the analysis (p=0.2). This find‐ ing is further supported by a survey study conducted in Olmstead County, Minnesota where residents demonstrating current or past smoking increased respondents' risk of

prevalent disorders worldwide and are particular problems in the United States [1,3]. Obesity is strongly related to major cardiovascular risk factors such as elevated blood pressure, glucose intolerance, type 2 diabetes and dyslipidemia. Prospective studies have shown a significant relationship between overweight or obesity and an increased rate of cardiovascular events. In a collaborative meta-analysis of 58 cohorts (221,934 people from 17 countries, 14,297 incident cardiovascular disease outcomes, 1.87 million person-years at risk), patients' risk of coronary heart disease, ischemic stroke and cardiovascular disease were found to increase by 29%, 20% and 23%, respectively, for every 4.56 kg/m<sup>2</sup> increase in body mass index after adjustment for

The mechanism behind the association between overweight/obesity and increased upper gastrointestinal symptoms is likely multifactorial [22]. First, the poor diet (ie, increased intake of fatty foods) [22] and lack of exercise that leads the overweight/obese state also promotes increased upper gastrointestinal symptoms (see further discussion below). Next, it is possible that abdominal obesity may lead to gastric compression by the surrounding adipose tissue. This causes increased intragastric pressure and relaxation of the lower esophageal sphincter, and ultimately heartburn and regurgitation. Obesity may also lead to the development of hiatal hernia promoting regurgitation symptoms. Lastly, humoral mechanisms related to obesity including increased levels of insulin, leptin, growth factors or hormones may contribute to

Results of the Domestic/International Gastroenterology Surveillance Study [3] suggested that the prevalence of upper gastrointestinal symptom reporting was higher in those with larger body mass indices. However, consistent with the proposed mechanisms listed above, it appeared the majority of the increased symptom burden related to increased body mass was

In a meta-analysis of 9 studies examining the association between body mass index and gastroesophogeal-like symptoms, six (67%) found a statistically significant association. Furthermore, data from 8 of the 9 studies demonstrated a "dose-response relationship" between body mass index and gastroesophageal symptoms, with an increase in the pooled adjusted odds ratios for symptoms of 1.43 (95% confidence interval, 1.158 to 1.774) for body mass index of 25 kg/m<sup>2</sup> to 30 kg/m<sup>2</sup> and 1.94 (95% confidence interval, 1.468 to 2.566) for body

) or obesity (body mass index ≥30 kg/m<sup>2</sup>

) are highly

gastroesophageal symptoms by 30-60% [25].

146 Dyspepsia - Advances in Understanding and Management

Overweight (body mass index ≥25 kg/m<sup>2</sup>

age, gender, and smoking status [26].

gastrointestinal symptoms as well [22,27].

[28].

gastroesophageal-like in nature.

mass index ≥ 30 kg/m<sup>2</sup>

**3.2. Overweight or obesity**

**Figure 2.** Prevalence of Upper Gastrointestinal Symptoms (By Subtype) By Body Mass Index in the Domestic/Interna‐ tional Gastroenterology Surveillance Study [3] Gastroesophogeal-like symptoms are the only symptom subtype trend‐ ing upwards with increasing body mass index

#### **3.3. Insufficient physical activity**

Current guidance [1,29] recommends all adults should do at least 150 minutes a week of moderate-intensity aerobic physical activity, 75 minutes a week of vigorous-intensity aerobic physical activity, or some equivalent combination of both in order to reduce their risk of heart disease and diabetes. In fact, maintaining this level of moderate- or vigorous-intensity physical activity each week has been associated with as much as a 30% decrease in ischemic heart disease risk and a similar reduction (27%) in the risk of developing diabetes. Unfortunately, nearly a third of people worldwide and a fifth of Americans do not meet this goal [1,3]. While the mechanism behind how insufficient physical activity/sedentary lifestyle is associated with upper gastrointestinal symptoms is unclear, it may be that there is a higher rate of overweight/ obesity in those who do not engage in enough physical activity, or the failure of inactive people to obtain the mental (reduced stress, reduced depressive symptoms and increased cognitive function) and bodily health benefits borne from physical activity [29].

Limited data evaluating the impact of physical activity on the prevalence of upper gastroin‐ testinal symptoms have been published in the medical literature. In an internet survey of over 2,500 respondents complaining of functional dyspepsia (or other gastrointestinal symptoms), only 6% of respondents reported exercising daily, 29% reported exercising at least once a week, and a majority (54%) claimed almost never or never exercising [30]. This was significantly less physical activity compared to a simultaneously surveyed control population (n=1,000) (p<0.01), suggesting that a sedentary lifestyle may be associated with an increased prevalence of upper gastrointestinal symptoms.

cardiovascular event. The treatment of both high cholesterol and high blood pressure often necessitates polypharmacy [32,33], and many of the drugs used to treat these conditions may

Upper Gastrointestinal Symptoms and Cardiovascular Disease

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149

There are conflicting data regarding the association between high cholesterol, high blood pressure and upper gastrointestinal symptoms. In one recent retrospective database analysis of 4-years' worth of data on 300,000 employees of companies in the United States-based, patients with ICD-9 codes for functional dyspepsia symptoms (n=1,669) were found to have a higher rate of both high cholesterol (prevalence rates of 21.2% versus 12.1%, p<0.05) and essential hypertension (17.8% versus 12.4%, p<0.05) compared to matched controls without upper gastrointestinal symptom coding (n=83,450) [9]. However, in a far older study examin‐ ing nearly 5,000 adults in the Rand Health Experiment, no statistically significant association was observed between either hypercholesterolemia or hypertension and patient reporting of

In 2008, the global prevalence of diabetes (fasting plasma glucose ≥ 126 mg/dL) was estimated to be 10%, resulting in approximately 1.3 million deaths. A diagnosis of diabetes increases patients' risk of cardiovascular disease by 2- to 3-fold, and consequently, cardiovascular

Diabetes may increase peoples' risk of having upper gastrointestinal complaints for a number of reasons. First, many medications used to treat diabetes and hopefully reduce patient's risk of both cardiovascular and microvascular (retinopathy, neuropathy, nephropathy) complica‐ tions can cause upper gastrointestinal symptoms including biguanides, sulfonylureas and alpha-glucosidase inhibitors [34]. Next, abnormal glucose regulation tends to occur in conjunction with other cardiovascular risk factors such as obesity, elevated blood pressure, low high-density lipoprotein cholesterol and a high triglyceride levels [1], as well as psychiatric disorders [35]; all known to be risk factors for upper gastrointestinal symptoms. Finally, the neuropathy associated with diabetes and resulting gastroparesis may cause diabetics to suffer from more upper gastrointestinal problems [35]. A recent prospective cohort study of 782 individuals found that *Helicobacter pylori* infection (a common cause of upper gastrointestinal symptoms) was associated with a 2.69-fold increased hazard of developing type II diabetes (95% confidence interval=1.10-6.60) [36], suggesting the relationship between diabetes and

Some studies support the association between diabetes and upper gastrointestinal symptoms. The Domestic/International Gastroenterology Surveillance Study demonstrated those suffer‐ ing from a metabolic or endocrine disorder (which would presumably include in large part, diabetes) were 2.6- to 4.4-fold more likely to report upper gastrointestinal symptoms in the prior three months (p<0.006)[8]. A study of Swedish type II diabetics (n=61) and non-diabetics (n=106) asked to complete a gastrointestinal symptom checklist found type II diabetes were more likely to report abdominal pain more often than once a month (28.3% versus 14.3%, p<0.01) and heartburn (31.77% versus 14.0%, p<0.05) [37]. Interestingly, it appears that the prevalence of upper gastrointestinal symptoms in diabetics may be linked to the extent/

"episodes or attacks of stomach pain or stomachache" in the prior 3-months [11].

disease accounts for approximately 60% of all diabetes-related deaths [1].

upper gastrointestinal symptoms may be bidirectional.

**3.6. Diabetes**

cause upper gastrointestinal symptoms (see further discussion below).

#### **3.4. Poor diet patterns**

Improper or poor diet has been shown to be an important risk factor for cardiovascular disease. From a strict cardiovascular viewpoint an ideal diet consists the consumption of ≥4.5 cups per day of fruits and vegetables, ≥2 servings a week of fish, and ≥3 servings per day of whole grains and no more than 36 ounces per week of sugar-sweetened beverages and 1500 mg per day of sodium [31]. In addition, other poor diet choices such as high dietary intake of saturated fat, trans-fat and cholesterol have also been tied to poor cardiovascular outcomes [1].

The failure to meet the above-mentioned dietary and lifestyle goals not only hinders a person's ability to achieve a healthy body weight, desirable cholesterol profile, and blood pressure, but has also been linked to increased rates of upper gastrointestinal complaints. In a retrospective database analysis [9] of employed Americans with functional dyspepsia determined by having an ICD-9 code of 536.8x (n=1,669) and matched controls (n=83,450), those found to have a nutritional deficiency (defined by the Agency of Healthcare Research and Quality's Clinical Classifications Software grouping of relevant ICD-9 codes) were 3.8-times as likely to complain of dyspeptic symptoms (p<0.05). Moreover, in the previously mentioned survey study of >2,500 respondents complaining of dyspeptic or irritable bowel symptoms and 1,000 controls [30], the irregular eating of meals was found to be associated with increased gastrointestinal complaints (p<0.05).

A handful of observational studies have also more specifically evaluated the individual contributions of various components of poor diet on upper gastrointestinal symptom preva‐ lence. An insufficient intake of vegetables has been found to be statistically significantly associated with increased gastrointestinal complaints (p<0.05) [30]. Moreover, in a sample of 1,000 employees of the United States Veteran's Administration system, a strong trend (p=0.09) towards an increased prevalence of heartburn and regurgitation symptoms (adjusted odds ratio=1.71, 95% confidence interval, 0.92-3.17) in those with high intake of saturated fat (measured using the 100-item Block Food Frequency Questionnaire) was also observed [22].

#### **3.5. High cholesterol and high blood pressure**

Ten percent of the world's adult population (and nearly 14% of the United States population) have high cholesterol (total cholesterol ≥240 mg/dL) and more than one-third of all people have high blood pressure (systolic and diastolic blood pressure ≥140 and 90 mm Hg, respectively), including 77.9 million American adults. Approximately one third of the global burden of ischemic heart disease can be attributed to high cholesterol, and each 20/10 mmHg increase in blood pressure, starting at 115/75 mmHg, has been shown to double a patients' risk of a cardiovascular event. The treatment of both high cholesterol and high blood pressure often necessitates polypharmacy [32,33], and many of the drugs used to treat these conditions may cause upper gastrointestinal symptoms (see further discussion below).

There are conflicting data regarding the association between high cholesterol, high blood pressure and upper gastrointestinal symptoms. In one recent retrospective database analysis of 4-years' worth of data on 300,000 employees of companies in the United States-based, patients with ICD-9 codes for functional dyspepsia symptoms (n=1,669) were found to have a higher rate of both high cholesterol (prevalence rates of 21.2% versus 12.1%, p<0.05) and essential hypertension (17.8% versus 12.4%, p<0.05) compared to matched controls without upper gastrointestinal symptom coding (n=83,450) [9]. However, in a far older study examin‐ ing nearly 5,000 adults in the Rand Health Experiment, no statistically significant association was observed between either hypercholesterolemia or hypertension and patient reporting of "episodes or attacks of stomach pain or stomachache" in the prior 3-months [11].

#### **3.6. Diabetes**

2,500 respondents complaining of functional dyspepsia (or other gastrointestinal symptoms), only 6% of respondents reported exercising daily, 29% reported exercising at least once a week, and a majority (54%) claimed almost never or never exercising [30]. This was significantly less physical activity compared to a simultaneously surveyed control population (n=1,000) (p<0.01), suggesting that a sedentary lifestyle may be associated with an increased prevalence

Improper or poor diet has been shown to be an important risk factor for cardiovascular disease. From a strict cardiovascular viewpoint an ideal diet consists the consumption of ≥4.5 cups per day of fruits and vegetables, ≥2 servings a week of fish, and ≥3 servings per day of whole grains and no more than 36 ounces per week of sugar-sweetened beverages and 1500 mg per day of sodium [31]. In addition, other poor diet choices such as high dietary intake of saturated fat,

The failure to meet the above-mentioned dietary and lifestyle goals not only hinders a person's ability to achieve a healthy body weight, desirable cholesterol profile, and blood pressure, but has also been linked to increased rates of upper gastrointestinal complaints. In a retrospective database analysis [9] of employed Americans with functional dyspepsia determined by having an ICD-9 code of 536.8x (n=1,669) and matched controls (n=83,450), those found to have a nutritional deficiency (defined by the Agency of Healthcare Research and Quality's Clinical Classifications Software grouping of relevant ICD-9 codes) were 3.8-times as likely to complain of dyspeptic symptoms (p<0.05). Moreover, in the previously mentioned survey study of >2,500 respondents complaining of dyspeptic or irritable bowel symptoms and 1,000 controls [30], the irregular eating of meals was found to be associated with increased gastrointestinal

A handful of observational studies have also more specifically evaluated the individual contributions of various components of poor diet on upper gastrointestinal symptom preva‐ lence. An insufficient intake of vegetables has been found to be statistically significantly associated with increased gastrointestinal complaints (p<0.05) [30]. Moreover, in a sample of 1,000 employees of the United States Veteran's Administration system, a strong trend (p=0.09) towards an increased prevalence of heartburn and regurgitation symptoms (adjusted odds ratio=1.71, 95% confidence interval, 0.92-3.17) in those with high intake of saturated fat (measured using the 100-item Block Food Frequency Questionnaire) was also observed [22].

Ten percent of the world's adult population (and nearly 14% of the United States population) have high cholesterol (total cholesterol ≥240 mg/dL) and more than one-third of all people have high blood pressure (systolic and diastolic blood pressure ≥140 and 90 mm Hg, respectively), including 77.9 million American adults. Approximately one third of the global burden of ischemic heart disease can be attributed to high cholesterol, and each 20/10 mmHg increase in blood pressure, starting at 115/75 mmHg, has been shown to double a patients' risk of a

trans-fat and cholesterol have also been tied to poor cardiovascular outcomes [1].

of upper gastrointestinal symptoms.

148 Dyspepsia - Advances in Understanding and Management

**3.4. Poor diet patterns**

complaints (p<0.05).

**3.5. High cholesterol and high blood pressure**

In 2008, the global prevalence of diabetes (fasting plasma glucose ≥ 126 mg/dL) was estimated to be 10%, resulting in approximately 1.3 million deaths. A diagnosis of diabetes increases patients' risk of cardiovascular disease by 2- to 3-fold, and consequently, cardiovascular disease accounts for approximately 60% of all diabetes-related deaths [1].

Diabetes may increase peoples' risk of having upper gastrointestinal complaints for a number of reasons. First, many medications used to treat diabetes and hopefully reduce patient's risk of both cardiovascular and microvascular (retinopathy, neuropathy, nephropathy) complica‐ tions can cause upper gastrointestinal symptoms including biguanides, sulfonylureas and alpha-glucosidase inhibitors [34]. Next, abnormal glucose regulation tends to occur in conjunction with other cardiovascular risk factors such as obesity, elevated blood pressure, low high-density lipoprotein cholesterol and a high triglyceride levels [1], as well as psychiatric disorders [35]; all known to be risk factors for upper gastrointestinal symptoms. Finally, the neuropathy associated with diabetes and resulting gastroparesis may cause diabetics to suffer from more upper gastrointestinal problems [35]. A recent prospective cohort study of 782 individuals found that *Helicobacter pylori* infection (a common cause of upper gastrointestinal symptoms) was associated with a 2.69-fold increased hazard of developing type II diabetes (95% confidence interval=1.10-6.60) [36], suggesting the relationship between diabetes and upper gastrointestinal symptoms may be bidirectional.

Some studies support the association between diabetes and upper gastrointestinal symptoms. The Domestic/International Gastroenterology Surveillance Study demonstrated those suffer‐ ing from a metabolic or endocrine disorder (which would presumably include in large part, diabetes) were 2.6- to 4.4-fold more likely to report upper gastrointestinal symptoms in the prior three months (p<0.006)[8]. A study of Swedish type II diabetics (n=61) and non-diabetics (n=106) asked to complete a gastrointestinal symptom checklist found type II diabetes were more likely to report abdominal pain more often than once a month (28.3% versus 14.3%, p<0.01) and heartburn (31.77% versus 14.0%, p<0.05) [37]. Interestingly, it appears that the prevalence of upper gastrointestinal symptoms in diabetics may be linked to the extent/ severity of their disease, with a large (n=1,101) cross-sectional survey study demonstrating higher adjusted odds of frequent abdominal pain (odds ratio=1.62, 95% confidence interval, 1.02-2.58), dysmotility-like dyspepsia (odds ratio=2.01, 95% confidence interval, 1.30-3.11), ulcer-like dyspepsia (odds ratio=1.49, 95% confidence interval, 0.90-2.45) and gastroesopha‐ geal reflux symptoms (odds ratio=2.28, 95% confidence interval, 1.54-3.38) in patients experi‐ encing a diabetes-related complication compared to those whom did not, and higher adjusted odds of dysmotility-like dyspepsia (odds ratio=1.32, 95% confidence interval, 1.08-1.60), ulcerlike dyspepsia (odds ratio=1.36, 95% confidence interval, 1.06-1.75) in those with poorer hemoglobin A1c control [38].

nal symptoms. An early study [54] of 110,469 upper endoscopies performed by 82 gastroen‐ terologists and 12 internists found a rate of 5 cardiopulmonary complications (not specifically defined) per 100,000 procedures performed. However, more recent studies in patients with stable coronary disease or those at risk for cardiovascular disease have observed much higher rates of cardiovascular complications following endoscopy. In a study of 71 patients with stable coronary heart disease undergoing endoscopy for evaluation for the safety of secondary prophylaxis with aspirin, 42% of patients experienced silent ischemia and one patient had a symptomatic event [40]. A second study utilizing data from 9 hospitals in the United States evaluated 602 charts for patients undergoing endoscopy and deemed to be at risk for cardio‐ vascular disease. The researchers found an overall cardiovascular complication (either an arrhythmia, hypotension, chest pain or angina equivalent, or myocardial infarction requiring intervention and occurring within one calendar day after the endoscopy) rate of one for every 325 procedures (or 308 complications per 100,000), and a rate as high as one complication for every 94 procedures (1,063 complications per 100,000) at the worst performing hospital [41]; a complication rate 2- to 70-fold higher than previously reported in the medical literature.

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The awareness of how the symptoms of cardiovascular diseases and upper gastrointestinal conditions overlap can improve the differential diagnosis, thus reducing the chance of

Optimal treatment of patients with cardiovascular disease [32,33] often requires the use of multiple medications. Consequently, at least some of the burden of upper gastrointestinal symptoms experienced in patients suffering from cardiovascular disease may be a result of polypharmacy. In the aforementioned Domestic/International Gastroenterology Surveillance Study [8], the occurrence of upper gastrointestinal symptoms was significantly higher in respondents reporting the use of a prescribed medication for another health problem com‐ pared to those not prescribed a medication (10.6% versus 6.0%, 5.1% versus 3.5% and 19.1% versus 13.3% for gastroesophogeal-, ulcer- and dysmotility-like symptoms, respectively, multivariate p<0.007 for all). Likewise, the use of an over-the-counter medication was also associated with a higher rate of upper gastrointestinal symptoms in general and dysmotility-

Numerous drugs indicated or commonly used to treat cardiovascular diseases including antiplatelets, antiarrhythmics, antihypertensives, antianginals, cholesterol-lowering medica‐ tions, as well as drugs to manage heart failure, diabetes and chronic kidney disease have been

Unfortunately, drug-induced dyspepsia can be difficult to identify because of the high background reporting of upper gastrointestinal symptoms. To overcome this problem, two studies [42,43,45] were conducted in a Dutch prescription database of over 1.5 million prescriptions (92 million person-years of follow-up) to identify signals for drug-induced dyspepsia using prescription sequence symmetry analysis methods. The basic principle

like symptoms (19.3% versus 13.2% and 33.9% versus 24.6%; p<0.0001 for both).

linked to the development of upper gastrointestinal symptoms.

inappropriate procedures and medications.

**5. Adverse effect of cardiovascular drugs**

Appropriate management of the overlapping risk factors can result in additional benefit to the patients. Of the many care management decisions to be made between the health care providers and the patients, an understanding of the risk factor pattern can help with the prioritization. These overlapping risk factors may deserve a higher priority, as they will improve both the cardiovascular and upper gastrointestinal conditions at the same time.

#### **4. Overlapping symptomatology and surveillance**

As many as 40% of people will complain of chest pain (along with associated symptoms of nausea, palpitations and shortness of breath) at least once in their lifetime [39,48]; however, symptoms reported by patients are typically unreliable for differentiating between chest pain of a cardiac or gastrointestinal (ie, dyspepsia, gastroesophageal reflux, peptic ulcer disease, pancreatitis, cholecystitis) origin [39,49]. Hence, the birth of famous adages such as, "*when a young man complains of pain in his heart, it is usually his stomach; when an old man complains of pain in his stomach, it is usually his heart"* [39]. Upper gastrointestinal symptoms, particularly gastroesophageal- or dysmotility-like dyspeptic symptoms, are a frequent cause of non-cardiac chest pain (ie, recurrent episodes of substernal chest pain in patients lacking a cardiac diagnosis after a comprehensive evaluation) [39]. This likely explains why as many as 55% of chest pain suffers presenting to the emergency room for the first time are not ultimately diagnosed with cardiovascular disease [50], and 30% of patients undergoing coronary angiography each year show no signs of coronary heart disease [51]. However, despite the lack of a cardiac diagnosis, up to 80% of non-cardiac chest pain sufferers continue to experience symptoms over time, and 25%-45% continue to take antianginal medications [52]. Thus, because of the critical and continual need to differentiate between cardiovascular disease and upper gastrointestinal symptoms in patients with chest pain, it would seem reasonable to assume the increased surveillance of one of these disorders would result in a higher rate of diagnosis of the other.

It has been suggested that in areas with a high prevalence of *H. pylori* infection, a "search and treat" strategy for ischemic heart disease patients with dyspepsia could significantly reduce the need for urgent postoperative endoscopy due to major gastrointestinal events [53]. However, endoscopy has been shown to induce cardiovascular complications, including myocardial ischemia [40,41,54]. Thus, this practice may serve as an additional explanation for the frequent diagnosis of cardiovascular disease in patients experiencing upper gastrointesti‐ nal symptoms. An early study [54] of 110,469 upper endoscopies performed by 82 gastroen‐ terologists and 12 internists found a rate of 5 cardiopulmonary complications (not specifically defined) per 100,000 procedures performed. However, more recent studies in patients with stable coronary disease or those at risk for cardiovascular disease have observed much higher rates of cardiovascular complications following endoscopy. In a study of 71 patients with stable coronary heart disease undergoing endoscopy for evaluation for the safety of secondary prophylaxis with aspirin, 42% of patients experienced silent ischemia and one patient had a symptomatic event [40]. A second study utilizing data from 9 hospitals in the United States evaluated 602 charts for patients undergoing endoscopy and deemed to be at risk for cardio‐ vascular disease. The researchers found an overall cardiovascular complication (either an arrhythmia, hypotension, chest pain or angina equivalent, or myocardial infarction requiring intervention and occurring within one calendar day after the endoscopy) rate of one for every 325 procedures (or 308 complications per 100,000), and a rate as high as one complication for every 94 procedures (1,063 complications per 100,000) at the worst performing hospital [41]; a complication rate 2- to 70-fold higher than previously reported in the medical literature.

The awareness of how the symptoms of cardiovascular diseases and upper gastrointestinal conditions overlap can improve the differential diagnosis, thus reducing the chance of inappropriate procedures and medications.

## **5. Adverse effect of cardiovascular drugs**

severity of their disease, with a large (n=1,101) cross-sectional survey study demonstrating higher adjusted odds of frequent abdominal pain (odds ratio=1.62, 95% confidence interval, 1.02-2.58), dysmotility-like dyspepsia (odds ratio=2.01, 95% confidence interval, 1.30-3.11), ulcer-like dyspepsia (odds ratio=1.49, 95% confidence interval, 0.90-2.45) and gastroesopha‐ geal reflux symptoms (odds ratio=2.28, 95% confidence interval, 1.54-3.38) in patients experi‐ encing a diabetes-related complication compared to those whom did not, and higher adjusted odds of dysmotility-like dyspepsia (odds ratio=1.32, 95% confidence interval, 1.08-1.60), ulcerlike dyspepsia (odds ratio=1.36, 95% confidence interval, 1.06-1.75) in those with poorer

Appropriate management of the overlapping risk factors can result in additional benefit to the patients. Of the many care management decisions to be made between the health care providers and the patients, an understanding of the risk factor pattern can help with the prioritization. These overlapping risk factors may deserve a higher priority, as they will improve both the cardiovascular and upper gastrointestinal conditions at the same time.

As many as 40% of people will complain of chest pain (along with associated symptoms of nausea, palpitations and shortness of breath) at least once in their lifetime [39,48]; however, symptoms reported by patients are typically unreliable for differentiating between chest pain of a cardiac or gastrointestinal (ie, dyspepsia, gastroesophageal reflux, peptic ulcer disease, pancreatitis, cholecystitis) origin [39,49]. Hence, the birth of famous adages such as, "*when a young man complains of pain in his heart, it is usually his stomach; when an old man complains of pain in his stomach, it is usually his heart"* [39]. Upper gastrointestinal symptoms, particularly gastroesophageal- or dysmotility-like dyspeptic symptoms, are a frequent cause of non-cardiac chest pain (ie, recurrent episodes of substernal chest pain in patients lacking a cardiac diagnosis after a comprehensive evaluation) [39]. This likely explains why as many as 55% of chest pain suffers presenting to the emergency room for the first time are not ultimately diagnosed with cardiovascular disease [50], and 30% of patients undergoing coronary angiography each year show no signs of coronary heart disease [51]. However, despite the lack of a cardiac diagnosis, up to 80% of non-cardiac chest pain sufferers continue to experience symptoms over time, and 25%-45% continue to take antianginal medications [52]. Thus, because of the critical and continual need to differentiate between cardiovascular disease and upper gastrointestinal symptoms in patients with chest pain, it would seem reasonable to assume the increased surveillance of one of these disorders would result in a higher rate of diagnosis of the other.

It has been suggested that in areas with a high prevalence of *H. pylori* infection, a "search and treat" strategy for ischemic heart disease patients with dyspepsia could significantly reduce the need for urgent postoperative endoscopy due to major gastrointestinal events [53]. However, endoscopy has been shown to induce cardiovascular complications, including myocardial ischemia [40,41,54]. Thus, this practice may serve as an additional explanation for the frequent diagnosis of cardiovascular disease in patients experiencing upper gastrointesti‐

**4. Overlapping symptomatology and surveillance**

hemoglobin A1c control [38].

150 Dyspepsia - Advances in Understanding and Management

Optimal treatment of patients with cardiovascular disease [32,33] often requires the use of multiple medications. Consequently, at least some of the burden of upper gastrointestinal symptoms experienced in patients suffering from cardiovascular disease may be a result of polypharmacy. In the aforementioned Domestic/International Gastroenterology Surveillance Study [8], the occurrence of upper gastrointestinal symptoms was significantly higher in respondents reporting the use of a prescribed medication for another health problem com‐ pared to those not prescribed a medication (10.6% versus 6.0%, 5.1% versus 3.5% and 19.1% versus 13.3% for gastroesophogeal-, ulcer- and dysmotility-like symptoms, respectively, multivariate p<0.007 for all). Likewise, the use of an over-the-counter medication was also associated with a higher rate of upper gastrointestinal symptoms in general and dysmotilitylike symptoms (19.3% versus 13.2% and 33.9% versus 24.6%; p<0.0001 for both).

Numerous drugs indicated or commonly used to treat cardiovascular diseases including antiplatelets, antiarrhythmics, antihypertensives, antianginals, cholesterol-lowering medica‐ tions, as well as drugs to manage heart failure, diabetes and chronic kidney disease have been linked to the development of upper gastrointestinal symptoms.

Unfortunately, drug-induced dyspepsia can be difficult to identify because of the high background reporting of upper gastrointestinal symptoms. To overcome this problem, two studies [42,43,45] were conducted in a Dutch prescription database of over 1.5 million prescriptions (92 million person-years of follow-up) to identify signals for drug-induced dyspepsia using prescription sequence symmetry analysis methods. The basic principle behind these types of analyses is that most patients complaining of drug-induced dyspeptic symptoms are empirically treated with anti-ulcer and/or anti-dysmotility agents; therefore, a drug's propensity for causing upper gastrointestinal symptoms might be reflected in the sequencing of anti-ulcer and/or anti-dysmotility agents relative to the other medication (eg, an excess of patients presenting with their first prescription for an anti-ulcer or dysmotility agent after compared to before the initiation of an index drug would suggest a possible dyspepsia-causing effect of the index drug). These studies identified a handful of (index) drugs to treat cardiovascular disease that were more often followed by (within 100-days), as compared to preceded by a histmaine-2-antagonist, proton pump inhibitor, bismuth prepara‐ tion, sucralfate, cispiride or metoclopramide. Drugs used to treat heart failure were among the drugs with the largest relative risks for upper gastrointestinal symptoms.

ACE=angiotensin-converting enzyme; NSAID=non-steroidal anti-inflammatory

geal symptom prevalence rates. [22,42,43,45].

**Table 6.** Cardiovascular Drugs Commonly Associated With Upper Gastrointestinal Symptoms

While a plausible explanation or underlying mechanism by which the abovementioned cardiovascular drugs can cause upper gastrointestinal symptoms is not always apparent, these drugs likely induce symptoms through direct mucosal irritation or injury (ie, aspirin and other non-steroidal anti-inflammatory drugs, potassium supplementation), facilitation of gastric acid reflux (ie, calcium channel blockers, nitrates) or alteration of gastric motility (ie, drugs targeting the renin-angiotensin system causing bradykinin-mediated dysmotility) [45,55]. Still yet, other associations between cardiovascular drugs and upper gastrointestinal symptoms may be "false" signals, representing nothing more than a link between a specific disease state or other confounder and upper gastrointestinal symptoms. Such may be the case with cholesterol-lowering medications. Patients with hypercholesterolemia may prefer frequent consumption of high-fat meals a well-known independent predictors of higher gastroesopha‐

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Similarly, while drugs commonly used to treat heart failure, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, loop diuretics and digoxin, have also been demonstrated in prescription sequence symmetry analyses to be upper gastrointestinal symptom-inducing; it is likely the symptoms attributed to them are a manifestation of heart failure itself (which has previously been shown to increase the risk of ulcer-like symptoms by as much as 3.6-fold [11]) and not the individual medications [11,57]. Of note, this may not always be the case with digoxin, which has been associated with dyspeptic-like symptoms in

Each year about 400,000 tons of aspirin (acetylsalicylic acid) are produced worldwide, and >50 million Americans take between 10 and 20 billion tablets for cardiovascular disease prevention [59]. Aspirin becomes non-ionized in the acidic environment of the gastrointestinal tract allowing it to penetrate mucosal tissue and cause irritation. Consequently it is not surprising that numerous studies have demonstrated aspirin to increase patients' relative risk of upper gastrointestinal symptoms by more than 2-fold over non-users [19-21,24,44]. Because of aspirin's frequent use and its propensity to cause gastric mucosal injury, it is likely the biggest drug-induced dyspepsia offender and one of the strongest links between upper gastrointesti‐ nal symptoms and cardiovascular disease. While it is best to stop aspirin in light of gastroin‐ testinal symptoms, there may be adverse cardiovascular consequences that need to be considered. A double-blind, placebo-controlled study evaluating low-dose aspirin users who experienced gastrointestinal bleeding compared continuation of aspirin with discontinuation [60]. Seventy-eight patients received aspirin 80 mg daily while 78 received placebo daily for 8 weeks. All patients received intravenous followed by oral proton pump inhibitor therapy (intravenous pantoprazole 80 mg bolus followed by 8 mg/hour for 72 hours then oral panto‐ prazole 40mg daily). Recurrent bleeding occurred in 10.3% of patients in the aspirin group vs. 5.4% of those in the placebo group (difference=4.9 points, 95% confidence interval=-3.6 to 13.4), p=not significant), but patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%, difference=11.6 points, 95% confidence

patients experiencing elevated/toxic blood concentrations (>2.0 ng/mL) [58].


This list was derived from searches of references 41,42,44,54,55

ACE=angiotensin-converting enzyme; NSAID=non-steroidal anti-inflammatory

behind these types of analyses is that most patients complaining of drug-induced dyspeptic symptoms are empirically treated with anti-ulcer and/or anti-dysmotility agents; therefore, a drug's propensity for causing upper gastrointestinal symptoms might be reflected in the sequencing of anti-ulcer and/or anti-dysmotility agents relative to the other medication (eg, an excess of patients presenting with their first prescription for an anti-ulcer or dysmotility agent after compared to before the initiation of an index drug would suggest a possible dyspepsia-causing effect of the index drug). These studies identified a handful of (index) drugs to treat cardiovascular disease that were more often followed by (within 100-days), as compared to preceded by a histmaine-2-antagonist, proton pump inhibitor, bismuth prepara‐ tion, sucralfate, cispiride or metoclopramide. Drugs used to treat heart failure were among the

drugs with the largest relative risks for upper gastrointestinal symptoms.

Amlodipine (and other calcium channel blockers) Antihypertensive, antianginal

Acetylsalicylic acid (and other NSAIDs) Antiplatelet

152 Dyspepsia - Advances in Understanding and Management

Amiodarone Antiarrhythmic

Atorvastatin (and other statins) High cholesterol

Bile acid sequestrants (less often with colesevelam) High cholesterol

Fibric acid derivatives (gemfibrozil>fenofibrate) High cholesterol

Niacin and nicotinic acid derivatives High cholesterol

Potassium supplements Dietary supplement

Nitrates Antianginal

This list was derived from searches of references 41,42,44,54,55

Non-aspirin antiplatelet agents (ie, cilostazol, ticlopidine) Antiplatelet

**Cardiovascular Drug(s) Common Cardiovascular Indication(s)**

Beta-blockers Antihypertensive, antianginal, heart failure

Fish oil preparations (ie, omega-3 fatty acids) High cholesterol, dietary supplement

Digoxin Atrial fibrillation, heart failure

Dronedarone Antiarrhythmic (atrial fibrillation)

Loop diuretics Heart failure, chronic kidney disease

Losartan Antihypertensive, heart failure, diabetes, chronic

Ramipril (and other ACE inhibitors) Antihypertensive, heart failure, diabetes, chronic

kidney disease

kidney disease

**Table 6.** Cardiovascular Drugs Commonly Associated With Upper Gastrointestinal Symptoms

While a plausible explanation or underlying mechanism by which the abovementioned cardiovascular drugs can cause upper gastrointestinal symptoms is not always apparent, these drugs likely induce symptoms through direct mucosal irritation or injury (ie, aspirin and other non-steroidal anti-inflammatory drugs, potassium supplementation), facilitation of gastric acid reflux (ie, calcium channel blockers, nitrates) or alteration of gastric motility (ie, drugs targeting the renin-angiotensin system causing bradykinin-mediated dysmotility) [45,55]. Still yet, other associations between cardiovascular drugs and upper gastrointestinal symptoms may be "false" signals, representing nothing more than a link between a specific disease state or other confounder and upper gastrointestinal symptoms. Such may be the case with cholesterol-lowering medications. Patients with hypercholesterolemia may prefer frequent consumption of high-fat meals a well-known independent predictors of higher gastroesopha‐ geal symptom prevalence rates. [22,42,43,45].

Similarly, while drugs commonly used to treat heart failure, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, loop diuretics and digoxin, have also been demonstrated in prescription sequence symmetry analyses to be upper gastrointestinal symptom-inducing; it is likely the symptoms attributed to them are a manifestation of heart failure itself (which has previously been shown to increase the risk of ulcer-like symptoms by as much as 3.6-fold [11]) and not the individual medications [11,57]. Of note, this may not always be the case with digoxin, which has been associated with dyspeptic-like symptoms in patients experiencing elevated/toxic blood concentrations (>2.0 ng/mL) [58].

Each year about 400,000 tons of aspirin (acetylsalicylic acid) are produced worldwide, and >50 million Americans take between 10 and 20 billion tablets for cardiovascular disease prevention [59]. Aspirin becomes non-ionized in the acidic environment of the gastrointestinal tract allowing it to penetrate mucosal tissue and cause irritation. Consequently it is not surprising that numerous studies have demonstrated aspirin to increase patients' relative risk of upper gastrointestinal symptoms by more than 2-fold over non-users [19-21,24,44]. Because of aspirin's frequent use and its propensity to cause gastric mucosal injury, it is likely the biggest drug-induced dyspepsia offender and one of the strongest links between upper gastrointesti‐ nal symptoms and cardiovascular disease. While it is best to stop aspirin in light of gastroin‐ testinal symptoms, there may be adverse cardiovascular consequences that need to be considered. A double-blind, placebo-controlled study evaluating low-dose aspirin users who experienced gastrointestinal bleeding compared continuation of aspirin with discontinuation [60]. Seventy-eight patients received aspirin 80 mg daily while 78 received placebo daily for 8 weeks. All patients received intravenous followed by oral proton pump inhibitor therapy (intravenous pantoprazole 80 mg bolus followed by 8 mg/hour for 72 hours then oral panto‐ prazole 40mg daily). Recurrent bleeding occurred in 10.3% of patients in the aspirin group vs. 5.4% of those in the placebo group (difference=4.9 points, 95% confidence interval=-3.6 to 13.4), p=not significant), but patients who received aspirin had lower all-cause mortality rates than patients who received placebo (1.3% vs. 12.9%, difference=11.6 points, 95% confidence interval=3.7 to 19.5). As such, if aspirin must be part of the regimen, like in settings where dual antiplatelet therapy is needed (cardiac stenting, post unstable angina and myocardial infarc‐ tion), treating the adverse gastrointestinal effects may be a superior strategy.


ACE=angiotensin-converting enzyme; ARR=adjusted rate ratios; CCBs=calcium channel blockers; CI=confidence inter‐ vals; H2A=histamine-2-antagonist; PPI=proton pump inhibitor; UGIS=upper gastrointestinal symptoms

rates of upper gastrointestinal symptoms [46,47,63]. In the largest systematic review to date (92 controlled trials), non-steroidals were found to increase the risk of dyspepsia versus placebo regardless of whether a strict (relative risk=1.36, 95% confidence interval=1.11-1.67) or liberal definition (relative risk= 1.19, 95% confidence interval=1.03-1.39) was used; with a placebo rate of 2.3% using the strict definition and 4.2% using the liberal definition [63].

**Table 7.** Percentages of Patients Taking Aspirin (75-325 mg/day) and Suffering Upper Gastrointestinal Symptoms Reporting Resolution of Symptoms Following 26-Weeks of Proton Pump Inhibitor (Esomeprazole 20 mg/day) Therapy

**UGIS PPI Group Placebo Group**

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Epigastric pain 83.9% 66.7%\*

Epigastric burning 72.7% 58.1%

Epigastric discomfort 68.3% 50.9%\*

Heartburn 89.7% 66.7%\*

Acid reflux 86.4% 56.5%\*

Nausea 92.6% 78.6%

Bloating 77.9% 66.1%

PPI=proton pump inhibitor; UGIS=upper gastrointestinal symptoms

\*p≤0.05

or Placebo [62]

In a systematic review of randomized controlled trials of adults with atrial fibrillation receiving pharmacologic stroke prevention, not only were upper gastrointestinal adverse effects found to be common place, but oral direct thrombin inhibitors were associated with highest inciden‐ ces of (~11%) and drug discontinuation due to these symptoms (~2%) [46]. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study found a statistically higher incidence of dyspepsia in patients receiving the oral direct thrombin inhibitor, dabigatran, compared to adjusted-dose warfarin (11.8% for dabigatran 110 mg, 11.3% for dabigatran 150 mg and 5.8% for warfarin, p<0.001 for the comparison of either dose of dabigatran versus warfarin)[47]. The dyspepsia-provoking nature of dabigatran has been attributed to its formulation which utilizes a tartaric acid core to lower the pH in the gastrointestinal tract and thus increase the absorption of the drug [47]. Luckily, there are Factor Xa inhibitors as therapeutic alternatives to direct thrombin inhibitors in those impacted by, or likely to be

Beyond the ability of cardiovascular drugs to provoke upper gastrointestinal symptoms, the occurrence of these symptoms may adversely affect cardiovascular drug adherence, putting

impacted by, upper gastrointestinal symptoms [56,64].

**Figure 3.** Results of Cardiovascular Drug Sequence Symmetry Analyses Using Histmaine-2-Antagonists, Proton Pump Inhibitors, Bismuth Preparations or Sucralfate, Cispiride or Metoclopramide. The cardiovascular sequence symmetry analyses depicted above assumed the development of one or more upper gastrointestinal symptoms was followed by (within 100 days) the prescription of a drug to treat it (eg, a histmaine-2-antagonist, proton pump inhibitors, bismuth preparation or sucralfate, cispiride or metoclopramide). Results were reported as the adjusted rate ratio of individuals with AN upper gastrointestinal symptom-treating drug prescribed last versus individuals with the upper gastrointesti‐ nal symptom-treating drug prescribed first. Ratios above 1.0 indicate a possible upper gastrointestinal symptom-in‐ ducing effect of the index cardiovascular drug.

Of note, while studies suggest enteric-coated or buffered formulations of aspirin provide no significant protective effect against gastrointestinal complications [61], randomized trials of patients taking aspirin suggest concomitant proton pump inhibitor therapy can both prevent upper gastrointestinal symptoms (p<0.05) [62] and reduce their prevalence in patients already suffering dyspeptic symptoms [44,62].

Aspirin is not, however, the only antithrombotic agent that has been associated with upper gastrointestinal symptoms. In fact, both non-aspirin antiplatelet agents (including other nonsteroidals, P2Y12 platelet inhibitors and phosphodiesterase inhibitors) and anticoagulants (particularly oral direct thrombin inhibitors) have been associated with clinically important


PPI=proton pump inhibitor; UGIS=upper gastrointestinal symptoms

interval=3.7 to 19.5). As such, if aspirin must be part of the regimen, like in settings where dual antiplatelet therapy is needed (cardiac stenting, post unstable angina and myocardial infarc‐

ACE=angiotensin-converting enzyme; ARR=adjusted rate ratios; CCBs=calcium channel blockers; CI=confidence inter‐

**Figure 3.** Results of Cardiovascular Drug Sequence Symmetry Analyses Using Histmaine-2-Antagonists, Proton Pump Inhibitors, Bismuth Preparations or Sucralfate, Cispiride or Metoclopramide. The cardiovascular sequence symmetry analyses depicted above assumed the development of one or more upper gastrointestinal symptoms was followed by (within 100 days) the prescription of a drug to treat it (eg, a histmaine-2-antagonist, proton pump inhibitors, bismuth preparation or sucralfate, cispiride or metoclopramide). Results were reported as the adjusted rate ratio of individuals with AN upper gastrointestinal symptom-treating drug prescribed last versus individuals with the upper gastrointesti‐ nal symptom-treating drug prescribed first. Ratios above 1.0 indicate a possible upper gastrointestinal symptom-in‐

Of note, while studies suggest enteric-coated or buffered formulations of aspirin provide no significant protective effect against gastrointestinal complications [61], randomized trials of patients taking aspirin suggest concomitant proton pump inhibitor therapy can both prevent upper gastrointestinal symptoms (p<0.05) [62] and reduce their prevalence in patients already

Aspirin is not, however, the only antithrombotic agent that has been associated with upper gastrointestinal symptoms. In fact, both non-aspirin antiplatelet agents (including other nonsteroidals, P2Y12 platelet inhibitors and phosphodiesterase inhibitors) and anticoagulants (particularly oral direct thrombin inhibitors) have been associated with clinically important

vals; H2A=histamine-2-antagonist; PPI=proton pump inhibitor; UGIS=upper gastrointestinal symptoms

ducing effect of the index cardiovascular drug.

suffering dyspeptic symptoms [44,62].

tion), treating the adverse gastrointestinal effects may be a superior strategy.

154 Dyspepsia - Advances in Understanding and Management

**Table 7.** Percentages of Patients Taking Aspirin (75-325 mg/day) and Suffering Upper Gastrointestinal Symptoms Reporting Resolution of Symptoms Following 26-Weeks of Proton Pump Inhibitor (Esomeprazole 20 mg/day) Therapy or Placebo [62]

rates of upper gastrointestinal symptoms [46,47,63]. In the largest systematic review to date (92 controlled trials), non-steroidals were found to increase the risk of dyspepsia versus placebo regardless of whether a strict (relative risk=1.36, 95% confidence interval=1.11-1.67) or liberal definition (relative risk= 1.19, 95% confidence interval=1.03-1.39) was used; with a placebo rate of 2.3% using the strict definition and 4.2% using the liberal definition [63].

In a systematic review of randomized controlled trials of adults with atrial fibrillation receiving pharmacologic stroke prevention, not only were upper gastrointestinal adverse effects found to be common place, but oral direct thrombin inhibitors were associated with highest inciden‐ ces of (~11%) and drug discontinuation due to these symptoms (~2%) [46]. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study found a statistically higher incidence of dyspepsia in patients receiving the oral direct thrombin inhibitor, dabigatran, compared to adjusted-dose warfarin (11.8% for dabigatran 110 mg, 11.3% for dabigatran 150 mg and 5.8% for warfarin, p<0.001 for the comparison of either dose of dabigatran versus warfarin)[47]. The dyspepsia-provoking nature of dabigatran has been attributed to its formulation which utilizes a tartaric acid core to lower the pH in the gastrointestinal tract and thus increase the absorption of the drug [47]. Luckily, there are Factor Xa inhibitors as therapeutic alternatives to direct thrombin inhibitors in those impacted by, or likely to be impacted by, upper gastrointestinal symptoms [56,64].

Beyond the ability of cardiovascular drugs to provoke upper gastrointestinal symptoms, the occurrence of these symptoms may adversely affect cardiovascular drug adherence, putting


least three drugs, and yield eradication rates of up to 90%. While the best *H. pylori* treatment regimen may vary depending on patient characteristics, guidelines recommended four different drug regimens including a proton pump inhibitor, clarithromycin, and amoxicillin, or metronidazole (clarithromycin-based triple therapy) for 14 days, a proton pump inhibitor or histamine-2-antagonist, bismuth, metronidazole, and tetracycline (bismuth quadruple therapy) for 10–14 days, or sequential therapy consisting of a proton pump inhibitor and amoxicillin for 5 days followed by a proton pump inhibitor, clarithromycin, and tinidazole for an additional 5 days (as an alternative to clarithromycin-based triple or bismuth quadruple

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157

Proton pump inhibitors competitively inhibit the cytochrome P450 2C19 isoenzyme (CYP2C19). Based on in vitro and in vivo data, omeprazole and esomeprazole are the most potent CYP2C19 inhibitors [69]. In vivo, omeprazole and esomeprazole induced 4 and 10 fold functional inhibition of CYP2C19 versus less than 1.5 fold inhibition with lansoprazole and pantoprazole [70]. Rabeprazole has in vitro data showing less inhibition of CYP2C19 than

Clopidogrel is a CYP2C19 substrate and needs to be activated by this isoenzyme. When given concurrently with proton pump inhibitors, there is a reduction in the produced active form of

Whether this platelet reactivity effect impacts clinical events has been controversial. A 2009 population-based study among Ontario residents aged 66 years or older used prescription records to ascertain proton pump inhibitor use during clopidogrel therapy. The analysis suggested that proton pump inhibitor use may be associated with an increased risk of cardiovascular events [odds ratio for recurrent myocardial infarction within 90 days following hospital discharge, 1.27 (1.03 to 1.57)], however, no effect on the risk of death was observed [odds ratio of death within 90 days following hospital discharge 0.82 (0.57 to 1.18)] [73]. The 16,718 patient Clopidogrel Medco Outcomes Study was a cohort evaluation from an integrated medical and pharmacy claims database. Patients had a clopidogrel prescription filled within one month of a coronary stenting procedure (where dual aspirin and clopidogrel therapy is frequently employed). Patients who concomitantly received a proton pump inhibitor were in the active group while those without were in the control group in this observational non‐ randomized study. Those receiving a proton pump inhibitor had more cardiovascular events (myocardial infarction, unstable angina, repeat coronary procedure) than those without (25% vs. 18%, p<0.0001). Without randomization, however, it cannot be ascertained where it was the underlying patient population with gastrointestinal symptoms that had a higher risk or if the use of the proton pump inhibitor yielded the difference. When patients on each proton pump inhibitor were analyzed separately, there were no differences in the percent of patients with a cardiac event: omeprazole 25%, esomeprazole 25%, lansoprazole 24%, and pantoprazole 29%. Given the marked differences in CYP2C19 inhibition between omeprazole and esome‐ prazole versus lansoprazole and pantoprazole, qualitative differences between the groups would have been expected [74]. Two other smaller analyses also supported the greater risk of cardiac events with patients receiving concurrent proton pump inhibitors but again, whether

omeprazole and lansoprazole but no in vivo data is available [69].

clopidogrel and greater platelet reactivity (less platelet inhibition) [71,72].

therapy) [68].

++=minimal risk (≤2%); +++=moderate risk (3-5%); ++++=high risk (5-10%)

ASA=aspirin; COX=cyclooxygenase; NSAID=non-steroidal anti-inflammatory drug; NA=not available; PDE=phospho‐ diesterase; UGIS=upper gastrointestinal symptoms

**Table 8.** Cross-Comparison of Upper Gastrointestinal Symptoms Precipitated by Antithrombotics [46,47,56,65]

patients at risk for adverse cardiovascular outcomes. Studies have demonstrated that gastro‐ intestinal side effects decrease medication adherence [66], and this likely plays an important role in the poor adherence often seen across the spectrum cardiovascular medications [67].
