Clin Drug Investig (2014) 34:83–93 DOI 10.1007/s40261-013-0135-4

ORIGINAL RESEARCH ARTICLE

Efficacy, Safety, and Tolerability of Pantoprazole Magnesium in the Treatment of Reflux Symptoms in Patients with Gastroesophageal Reflux Disease (GERD): A Prospective, Multicenter, Post-Marketing Observational Study Jose´ Marı´a Remes-Troche • Sergio Sobrino-Cossı´o • Julio Ce´sar Soto-Pe´rez • Oscar Teramoto-Matsubara • Miguel Morales-Ara´mbula • Antonio Orozco-Gamiz Jose´ Luis Tamayo de la Cuesta • Gualberto Mateos

•

Published online: 18 December 2013 Ó Springer International Publishing Switzerland 2013

Abstract Background To improve proton pump inhibitor effects, pharmacological modifications have been developed such as the use of enantiomer molecules (e.g., S-omeprazole, S-pantoprazole, or dexlansoprazole), or addition of NaHCO3 (for an immediate release) or magnesium (with a lower absorption for a more sustained effect). Objective The objective of this study was to assess the efficacy, safety, and tolerability of pantoprazole magnesium 40 mg once daily for 4 weeks, on the relief of reflux symptoms in gastroesophageal reflux disease (GERD) patients. Methods A phase IV, open-label, prospective, multicenter study was designed. Patients included were prescribed pantoprazole magnesium 40 mg orally once daily for 28 ± 2 days. All patients had a history of persistent or recurrent heartburn and/or acid regurgitation for at least 3 months. Effectiveness and tolerability data obtained from

patients who completed a minimum of 4 weeks of pantoprazole magnesium treatment were considered for analysis. Results The account of baseline characteristics and demographics of GERD symptom intensity was made by analyzing the group of 4,343 patients that fulfilled all inclusion criteria; 54 % were females (n = 2,345) and 46 % (n = 1,998) males, with a mean age of 36.2 ± 7.5 years. Severity of symptoms, assessed by the physician using the 4-point Likert scale, reduced by at least 80 % from baseline intensity after treatment in the per protocol population. In the case of the intention-to-treat population, the improvement in symptom intensity was 73 %. The number of patients that experienced any adverse events was 175/5,027 (3.48 %). Conclusions Pantoprazole magnesium is a safe, effective, and well-tolerated drug that significantly improves GERD symptoms.

J. M. Remes-Troche (&) Digestive Physiology and Motility Lab, Instituto de Investigaciones Me´dico Biolo´gicas, Universidad Veracruzana, Iturbide SN. Col Centro, Veracruz, VER 91400, Mexico e-mail: [email protected]; [email protected]

M. Morales-Ara´mbula Unidad de Gastroenterologı´a Hospital Privado, Guadalajara, JAL, Mexico

S. Sobrino-Cossı´o ´ ngeles del Pedregal, Servicio de Endoscopia, Instituto Hospital A Nacional de Cancerologı´a, Mexico City, Mexico J. C. Soto-Pe´rez Clı´nica de Fisiologı´a Digestiva del Hospital Metropolitano, Servicio de Gastroenterologı´a y Endoscopia del Hospital Central Sur de Alta Especialidad PEMEX, Mexico City, Mexico O. Teramoto-Matsubara Unidad de Gastroenterologı´a y Motilidad Palmas, Mexico City, Mexico

A. Orozco-Gamiz GastroLab, Guadalajara, Jalisco, Mexico J. L. Tamayo de la Cuesta ´ ngeles Culiaca´n, Hospital Civil de Culiaca´n CIDOCS, Hospital A Culiaca´n, Sinaloa, Mexico G. Mateos Hospital Angeles del Pedregal, Mexico City, Mexico

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1 Introduction Gastroesophageal reflux disease (GERD) is one of the most frequent causes for seeking medical care, both in general and gastroenterology practice [1, 2]. The significance of this illness is based on its high prevalence and on the potential consequences that it may have both in the shortand long-term. Proton pump inhibitors (PPIs), which are benzimidazole and imidazopyridine derivatives, have changed the natural history of acid-related disorders (peptic ulcer, erosive gastropathy, and GERD) [3, 4]. During the last two decades, the superiority of PPIs over other drugs (antacids, prokinetics, and histamine H2-receptor antagonists) has been established beyond doubt by many pharmacological studies and large clinical trials [5, 6]. Today, PPIs are considered to be the mainstay of antireflux medical therapy and are extensively prescribed, not only by gastroenterologists but also by non-gastrointestinal specialists such as cardiologists, pneumologists, or otorhinolaryngologists [5–7]. While all of the PPIs are effective in the long-term, studies have shown variable rates in intragastric pH control and symptomatic response in the short-term [8–10]. The decision of choosing a PPI should be based on efficacy, safety, tolerability, quality of life, pharmacogenomics, and cost effectiveness [8–11]. In the evolution of PPIs, omeprazole was the first PPI molecule available (1989) [12]. Lansoprazole (1995), rabeprazole (1999), and pantoprazole (2000) were subsequently introduced in the market [13]. With the objective of improving PPI effects, pharmacological modifications have been developed such as the use of enantiomer molecules (e.g., S-omeprazole, S-pantoprazole, or dexlansoprazole), or addition of NaHCO3 (for an immediate release) or magnesium (with lower absorption for a more sustained effect) [14]. Delayed-release formulations such as encapsulated enteric-coated granules or tablets (omeprazole, pantoprazole, rabeprazole, and dexlansoprazole) have also been used for a more prolonged effect by making them dual or multiple formulations so that the active substance, irrespective of the dose, is available for absorption for an extended period of time [12, 14, 15]. Pharmacokinetic analyses indicate that the elimination half-life of pantoprazole magnesium is 23 % longer than that of pantoprazole sodium [16]. These differences in pharmacokinetic parameters are likely due to the slow dissolution of the magnesium-containing tablets in the stomach, resulting in reduced solubility. In a double-blinded, randomized, controlled multicentric trial (n = 636), Hein [17] found that pantoprazole magnesium is clinically as effective and well-tolerated as pantoprazole sodium in the treatment of GERD stages I–III, demonstrating non-

J. M. Remes-Troche et al.

inferiority for esophageal healing at 8 weeks and superior healing rates at 4 weeks associated with high levels of symptomatic relief. Although there are slight differences in the pharmacokinetics of pantoprazole sodium and pantoprazole magnesium, their pharmacodynamic features and safety profiles are similar, and showed no apparent qualitative or quantitative differences in the toxicity or drug–drug interaction profiles of the two formulations [17]. It is important to remark that, recently, several studies have reported the possible interaction of clopidrogel and PPIs leading to a decrease in the antiplatelet efficacy of clopidrogel [18]. However, pantoprazole is a PPI not associated with the decrease in the antiplatelet efficacy of clopidrogel [19]. The primary objective of this study was to assess the efficacy, safety, and tolerability of TectaÒ (Nykomed, Me´xico City, Mexico) [pantoprazole magnesium 40 mg orally, once daily for 4 weeks] on the relief of reflux symptoms (i.e., heartburn, acid regurgitation, epigastric pain, night-time epigastric discomfort, etc.) in GERD patients. Also, as part of the study, the usefulness of the self-administered reflux symptom questionnaire ReQuestÒ (Spanish version) was assessed in Mexican patients [20, 21].

2 Methods A phase IV, open-label, prospective, observational, descriptive, multicenter study was designed. It was carried out according to the observational or non-interventional clinical study definition described in Directive 2001/20/EC [22], and its follow-up was carried out in accordance with the good clinical and epidemiological practice guidelines. The main feature of this kind of study is that all patients receive the study medication, which allows investigation of what happens in daily practice. This study was approved by the Ethical Committee of Research of the Dr. Maximiliano Ruiz Castan˜eda General Hospital of Naucalpan, and the Center of Bioethics of the Medicine Faculty of the University of Guanajuato, Mexico. The study medication was pantoprazole magnesium 40 mg (TectaÒ), which was given according to the product prescribing information approved by the local health authorities. Patients participating in this study were prescribed pantoprazole magnesium 40 mg orally once daily for 28 ± 2 days. As shown in Table 1, the study comprised two visits in total: V0—in which patients were screened and enrolled in the study; and V1—the study’s final visit. The procedures performed on each visit are described in Table 1.

Pantoprazole Magnesium in Symptomatic GERD Table 1 Study schedule and recorded parameters

CRF clinical research form, GERD gastroesophageal reflux disease

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Parameter

Visit 0 (day 0)

Visit 1 (day 28 ± 2 days)

Verification of the inclusion/exclusion criteria

X

Signed informed consent

X

Demographic data

X

Complete medical history

X

GERD symptom assessment by the investigator

X

X

Complete general physical examination

X

X

Concomitant medications

X

X

Endoscopic procedure (optional/at the discretion of the investigator)

X

Dispensing of study medication to the patient

X

Dispensing of the ReQuestÒ and use instructions to the patient

X

X

Treatment compliance evaluation Complete evaluation of adverse events

X X

Collection of boxes and blisters of study medication

X

Return of CRF and questionnaires

X

2.1 Patient Population 2.1.1 Inclusion Criteria Prior to their inclusion in the study, patients signed and dated the informed consent together with two witnesses and the investigator. In order to participate in the study, male and female outpatients, between the ages of 18 and 50 years old, fulfilling the following clinical criteria were included: (a) history of persistent or recurrent episodes (three or more episodes per week) of heartburn and/or acid regurgitation for at least 3 months, not necessarily consecutive, within the last 12 months, and with one or more of the following related symptoms: burping, belching, water brash, globus (feeling of a lump in the esophagus), dysphagia, odynophagia, retching, early satiety, nausea, retrosternal pain, dysphonia or hoarseness; and (b) found to have no evidence of structural disease likely to explain their symptoms, using the alarm signs referred to below and/or according to endoscopy findings. Endoscopy was performed in patients according to the investigator criteria to exclude organic disease or in cases with long-standing symptoms (more than 5 years).

confirmed esophageal strictures, grade C or D esophagitis from the Los Angeles classification, diverticula or varices, achalasia or Barrett’s esophagus; (c) patients with a history of peptic ulcer and/or its complications (e.g., bleeding, strictures, etc.); (d) patients with previous esophageal/ upper gastrointestinal surgery (exception: cholecystectomy); (e) patients with a history of Zollinger-Ellison syndrome or other gastric hypersecretory condition; (f) cardiovascular (e.g., angina pectoris, myocardial infarction, ventricular extrasystoles), pulmonary, endocrine, renal or hepatic disease, hematological disorders, or any other medical condition that could increase the risk to participating patients; (g) malignant disease of any kind in any system or organ; (g) pregnant or nursing women; and (h) women of childbearing potential who had not been using a reliable and clinically acceptable birth control method (e.g., intrauterine contraceptive device, oral or injectable contraceptives) within at least 3 months. The following restrictions were applied regarding previous medications: (a) PPIs within 14 days prior to study start; (b) H2-receptor antagonists or prokinetics within 7 days prior to study start; and (c) history of treatment for Helicobacter pylori eradication within 28 days prior to study start.

2.1.2 Exclusion Criteria 2.2 Dosing Regimen The following exclusion criteria were applied during the patients’ initial visit: (a) patients with suspected or confirmed alarm signs related to their illness (e.g., progressive and/or chronic dysphagia, persistent odynophagia, involuntary weight loss, anorexia, anemia, palpable nodules or mass, fever of unknown etiology, gastrointestinal bleeding, etc.) within 3 months prior to study start; (b) suspected or

All patients participating in the study received two boxes of pantoprazole magnesium 40 mg during their initial visit (V0), each containing two cardboard wallets scheduled for every day of the week, each of them wrapped an aluminum blister which in turn contained seven tablets of pantoprazole magnesium 40 mg.

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2.3 Study Protocol During the initial visit (V0), participating physicians assessed the inclusion and exclusion criteria so as to decide whether or not a patient should be invited to participate in the study. Once a patient was assessed as eligible, the investigator explained the Informed Consent contents to the patient who voluntarily agreed to participate by signing and dating the Informed Consent. Complete medical history and physical examination were performed, and patients were asked if they had any illnesses concomitant to the current disease and if they were or had been receiving any treatment. All of the information provided by patients was recorded in a clinical research form (CRF). Regarding the current disease, which was the reason for participating in this study, investigators asked questions on the occurrence of typical and related GERD symptoms, using a 4-point Likert scale (0 = none, 1 = mild or hardly perceptible symptoms, with only slight general discomfort, 2 = moderate or clearly perceptible symptoms, but tolerable without demanding immediate relief, and 3 = severe or overwhelming discomfort, urging immediate relief). To record the patient personal assessment of their symptoms, they received and were instructed on the use of a ReQuestÒ (‘‘Reflux Questionnaire’’) notebook for symptom self-assessment. The questionnaire was completed at the end of the day, daily from day 1 to 7 after the first dose, and then at days 14, 21, and 28. Any doubts patients had were clarified so properly assessed and recorded data could be obtained. Investigators emphasized how important it was that patients returned the notebook on their next visit. ReQuestÒ is a self-administered questionnaire developed and validated to assess the treatment effect on GERD symptom evolution. This symptom measurement tool was developed after countless reviews of the medical literature on GERD and its symptoms, re-analyses of clinical trials, participation of several worldwide expert gastroenterologists, and extensive interviews of GERD patients [21, 22]. A total of 67 descriptions of typical and atypical gastroesophageal reflux symptoms were grouped in six different GERD categories or dimensions: (1) dimension of acid-related symptoms or complaints; (2) dimension of upper abdominal/ stomach symptoms or complaints; (3) dimension of lower abdominal/digestive symptoms or complaints; (4) dimension of nausea; (5) dimension of sleep disturbances; and (6) dimension of other symptoms or complaints [23]. To these six dimensions, a last dimension was added: the general wellbeing dimension. Each dimension was evaluated to validate the frequency (by means of a 7-point Likert scale) and intensity (by means of a 100-mm visual analog scale) of every corresponding symptom, except for the general wellbeing dimension, which was only evaluated for intensity.

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Study medication was dispensed to patients and how and for how long it was to be taken was explained. Patients took their first dose in the presence of the investigator and were asked to come back for their next visit (V1), during which they had to return all boxes and blisters with any remaining tablets, along with their ReQuestÒ symptom assessment notebook. During the patient final visit (V1), within 28 ± 2 days, the following was performed: (a) complete general physical examination (including anthropometrics); (b) questions on concomitant medication intake; (c) GERD symptom assessment by the investigator (4-point Likert scale); (d) treatment compliance evaluation through collection and accountability of unused study medication; and (e) review of the ReQuestÒ filled in by the patient. 2.4 Outcome Measurements Effectiveness and tolerability data obtained from patients who completed a minimum of 4 weeks of pantoprazole magnesium treatment were considered for analysis. The treatment response rate after 4 weeks was measured by comparing symptom assessment (4-point Likert scale) and ReQuestÒ scores at the end of treatment with baseline scores. An adverse event was defined as any untoward medical occurrence in a patient, regardless of whether it was considered to be causally related to use of the treatment. An adverse event could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product. Among laboratory findings, liver function tests, glucose and creatinine determinations were performed according to the physician criteria. Adverse events data were collected throughout the study and until 30 days after the last dose. At the end of the study the medication was stopped All adverse events, including symptoms, signs, or diseases, were evaluated. Information recorded concerning the adverse events occurring during the trial period included their nature, whether serious or not, their intensity, any treatment given, the outcome, and an opinion about the causal relationship with the study medication. The incidence (%) of adverse events was calculated and analyzed according to the guidelines for statistical analysis issued by the Drug Safety Department in Mexico (COFEPRIS, Me´xico City, Mexico). The seriousness of the adverse event and its causal relationship with treatment were also tabulated. Furthermore, information on adverse reactions, defined as adverse events considered to be causally related to use of the study drug, was recorded in detail. A list of all adverse events was compiled.

Pantoprazole Magnesium in Symptomatic GERD

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2.5 Statistical Analysis Sample demographic characteristics were summarized using descriptive statistics; for this purpose, percentages, odds ratios (ORs), and 95 % confidence intervals were calculated. The efficacy analysis was performed using a multivariate analysis of covariance (MANCOVA) for repeated samples; time was considered as the principal related (nested) factor and fitted variables were patient sex, age, body mass index (BMI), and place of residence. Epsilon calculations were made in each model to determine whether or not the assumption of sphericity was met, and if not met the degrees of freedom were corrected using the Huynh–Feldt or Greenhouse–Geisser method [24]. Cook’s distances and leverage points were also analyzed to detect multivariate outlier values. The correlation between heartburn and regurgitation scores recorded on the Likert scale (assessed by physicians/investigators) and those recorded on the ReQuestÒ notebook (assessed by patients) was calculated using two different approaches: Somer’s d asymmetric measure of association between two variables and Spearman’s rho. The software used for data management was SASÒ (Statistical Analysis Software, SAS Statistical Institute Inc., Cary, NC, USA) version 9.1. For statistical analysis, the software used was SPSSÒ (Statistical Package for Social Sciences, IBM, Chicago, IL, USA) version 15 and StatisticaTM (Statsoft, Tulsa, OK, USA) version 6.0.

Fig. 1 Depletion of the database sample to form the safety and efficacy intention-to-treat populations. ITT intention-to-treat

3 Results 3.1 Population A total of 5,092 patients were enrolled in the study from 1,306 practices around the country. Sixty-five subjects were removed because they did not sign their Informed Consent authorizing the use of collected data (Fig. 1). The inclusion criteria to define this analysis population was that patients had taken at least one dose of study medication. This population included a total of 5,027 patients that were analyzed to obtain safety data and it was designated the ‘‘safety intention-to-treat (ITT) population’’. During analysis, 684 patients from this group were found to be protocol violators as they had at least one exclusion criterion in the enrollment visit (V0), e.g., the patient did not have heartburn and/or regurgitation, the patient’s age was outside of the protocol-defined age range, or the patient had esophageal mucosal breaks grade C or D according to the Los Angeles classification, as evidenced by endoscopy data recorded on the CRF. After removing the 684 patients classified as protocol violators, the efficacy ITT population was conformed resulting in a total of 4,343

Fig. 2 Depletion of the efficacy intention-to-treat population to form the efficacy per protocol population. Some patients were excluded for more than one reason. ITT intention-to-treat, PP per protocol

patients. These patients fulfilled all of the inclusion criteria, but some had missing data. The last recorded observation was used as if it had remained unchanged throughout the study [last observation carried forward (LOCF) approach]. This was the ITT population used to measure the study medication efficacy. From the 4,343 patients included in the efficacy ITT population, 678 (15.6 %) patients were removed from the efficacy ITT analysis, leaving 3,665 in the efficacy per protocol (PP) analysis (Fig. 2).

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3.2 Demographics

3.4 Endoscopy Findings

The baseline characteristics and demographics of GERD symptom intensity for the study sample were determined by analyzing the group of 4,343 patients that fulfilled all inclusion criteria. There were 54 % females (n = 2,345) and 46 % (n = 1,998) males with a mean [± standard deviation (SD)] age of 36.2 ± 7.5 years, and a BMI above normal for both sexes (26.3 ± 4.3 kg/m2). At the time of the clinical interview 6 % (n = 260) were smokers, while 4.1 % were declared to be ex-smokers.

Endoscopy was performed in 917 patients (21 %), and 54 % were females (n = 495). The mean (± SD) age was 36.6 ± 7 years for males and 37.2 ± 7.2 (p \ 0.228) for females. The BMI for males was higher than for females (26.8 ± 3.5 vs. 25.2 ± 4.5; p \ 0.001), and males were prone to have a BMI greater than 30 (OR = 1.94, 95 % CI 1.3–2.9). According to the Los Angeles classification, 197 (21 %) had non-erosions, 435 (47 %) had grade A esophagitis, 235 (28 %) had grade B esophagitis, and 32 (4 %) grades C–D.

3.3 Baseline Symptoms 3.5 Efficacy Analysis Among atypical and extra-esophageal GERD symptoms, upper abdominal/epigastric pain showed the highest prevalence (90.6 %) and was not sex-related. The second most prevalent symptom was burping/belching (88.3 %), being slightly predominant in men (OR = 1.32; p \ 0.003). Subsequent symptoms that showed a lower but clinically significant prevalence are shown in Table 2. Men showed a higher probability of having chronic cough than women, while women showed a higher probability of having globus and retching than men. The maximum number of GERD-related symptoms a patient could have according to the CRF was 16 (sum of all GERD-related symptoms), and approximately 7 % of the patients had all these symptoms. On the other hand, 7 % of the patients had only three or fewer GERD-related symptoms.

Severity of symptoms assessed by the physician using the 4-point Likert scale had a reduction of at least 80 % from baseline intensity after treatment in the PP population (Table 3). In the case of the ITT population, the average improvement for symptom intensity was 73 %. Using the ReQuestÒ, percentage changes in improvement of symptom intensity were highest at the end of the first week: between 51 and 58 % for the PP population, and between 37 and 45 % for the ITT population. From week 2 on, there was an additional improvement of 15–19 % for the PP group, and 10–12 % for the ITT group (Table 4; Figs. 3 and 4). These findings suggest that when a subject complies with the treatment, a 71.56 % reduction is expected in symptom intensity as measured by the

Table 2 Gastroesophageal reflux disease symptom frequency and sex-related odds ratio Symptom

Frequency [n (%)]

M/F (n)

OR for men

95 % CI

p value 0.003

Burping

4,015 (88.3)

1,879/2,136

1.32*

1.10–1.59

Sialorrhea

2,164 (47.6)

974/1,190

0.93

0.83–1.04

0.204

Globus Dysphagia

2,553 (56.2) 2,242 (49.3)

1,115/1,438 1,012/1,230

0.81* 0.93

0.72–0.91 0.83–1.05

\0.001 0.252

Odynophagia

1,718 (37.8)

762/956

0.90

0.80–1.01

0.083

Retching

1,727 (38.0)

734/993

0.80*

0.71–0.90

\0.001

Halitosis

2,663 (58.6)

1,231/1,432

1.02

0.91–1.15

0.712

Epigastric pain/discomfort

4,118 (90.6)

1,876/2,242

0.83

0.68–1.01

0.065

Early satiety

2,945 (64.8)

1,284/1,661

0.76*

0.67–0.86

\0.001

Nausea

3,088 (67.9)

1,280/1,808

0.57*

0.50–0.64

\0.001

Flatulence

2,830 (62.3)

1,315/1,515

1.05

0.93–1.19

0.414

Non-cardiac retrosternal pain/tightness

3,024 (66.5)

1,363/1,661

0.90

0.79–1.01

0.078

Dyspnea

1,136 (25.0)

501/635

0.90

0.79–1.03

0.139

Chronic cough

1,498 (33.0)

723/775

1.15*

1.01–1.30

0.031

Dysphonia

1,655 (36.4)

766/889

1.02

0.90–1.15

0.769

Sleep disturbances

2,902 (63.8)

1,316/1,586

0.93

0.82–1.05

0.244

ORs with an asterisk were statistically significant. If an OR value is\1 it means that women are at higher odds of having that symptom than men; meanwhile, if an OR value is [1, men are at higher odds of having that symptom than females F female, M male, OR odds ratio

Pantoprazole Magnesium in Symptomatic GERD

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Table 3 Change in gastroesophageal reflux disease symptom severity from baseline to day 28 of the study, as assessed by physicians using an ordinal Likert scale Symptom

n

Baseline Mean

Day 28 SEM

Mean

p value

Change (%)

SEM

Heartburn

4,295

2.25

0.01

0.63

0.01

\0.0001

-72.03

Acid regurgitation

4,254

2.17

0.01

0.57

0.01

\0.0001

-73.70

Burping/belching Water brash/sialorrhea

4,019 3,442

1.68 0.91

0.01 0.02

0.49 0.22

0.01 0.01

\0.0001 \0.0001

-70.75 -75.46

Globus

3,524

1.09

0.02

0.30

0.01

\0.0001

-72.48

Dysphagia

3,495

0.89

0.02

0.22

0.01

\0.0001

-74.87

Odynophagia

3,278

0.70

0.02

0.15

0.01

\0.0001

-78.38

Retching

3,299

0.70

0.02

0.18

0.01

\0.0001

-74.73

Halitosis

3,601

1.17

0.02

0.37

0.01

\0.0001

-68.19

Epigastric pain/discomfort

4,164

1.98

0.01

0.55

0.01

\0.0001

-72.18

Early satiety

3,655

1.35

0.02

0.37

0.01

\0.0001

-72.37

Nausea

3,775

1.23

0.02

0.31

0.01

\0.0001

-74.91

Flatulence

3,597

1.34

0.02

0.46

0.01

\0.0001

-65.84

Non-cardiac chest pain/tightness

3,672

1.37

0.02

0.32

0.01

\0.0001

-76.34

Dyspnea

3,157

0.50

0.02

0.14

0.01

\0.0001

-72.61

Chronic cough

3,320

0.66

0.02

0.18

0.01

\0.0001

-72.86

Dysphonia

3,315

0.69

0.02

0.18

0.01

\0.0001

-73.65

Sleep disturbances

3,726

1.35

0.02

0.38

0.01

\0.0001

-71.60

SEM standard error of the mean

Table 4 Change in the ReQuestÒ dimensions from baseline to day 7 and day 28 of the study

Symptoms General well-being Acid complaints Upper abdominal complaints Lower abdominal complaints Nausea Sleep disturbances

ReQuestÒ. Instead, a subject for whom it is unknown if he/ she will have treatment compliance of at least 85 %, will have a 52 % reduction in symptom intensity as measured by the ReQuestÒ. The agreement between physician and patient assessments of heartburn was analyzed. Since both scales are asymmetric, Somer’s d (0.2; p \ 0.001) and Spearman’s rho (q = 0.21; p \ 0.001) coefficients were used to analyze agreement correlation. Both measurements suggest a poor correlation between these two variables.

Evaluation period (days)

Per protocol

Intention-to-treat

7

-56.36

-43.11

28

-75.20

-56.25

7

-58.99

-45.23

28

-76.71

-57.23

7

-57.96

-44.04

28

-75.01

-55.38

7

-51.36

-37.78

28

-68.20

-49.07

7

-52.33

-37.61

28

-67.62

-47.29

7

-51.83

-37.49

28

-67.83

-47.99

3.6 Safety Analysis The ITT population was considered for the safety analysis as all of these patients took at least one dose of the study medication. The number of patients that experienced any events during the study was 175/5,027 (3.48 %) patients with 232 adverse events. The most common adverse events were diarrhea (0.57 %, n = 29), nausea (0.51 %, n = 26), dizziness (0.33 %, n = 17), headache (0.31 %, n = 16), and constipation (0.21 %, n = 11). The 232 reported

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adverse events were classified into four categories: unrelated to treatment (n = 106), unlikely related to treatment (n = 34), likely related to treatment (n = 72), and definitively related to treatment (n = 20). The physician’s clinical criterion was the most important factor for patient classification. For study report purposes, only those adverse events and patients with a likely and definitive relation are described. From the evaluation of definitive and likely causal relation, only 70/5,027 (1.39%) patients experienced 92 events that were causally related to study medication. The most common related adverse effects were diarrhea

Fig. 3 Changes in the general well-being score for per protocol and intention-to-treat populations; the lower the value, the greater the well-being. The Y axis shows symptom intensity score by ReQuestÒ. The graph shows mean scores. ITT intention-to-treat, PP per protocol Fig. 4 Changes in a acid complaints, b upper and c lower abdominal complaints, and d nausea scores for per protocol and intention-to-treat populations; the lower the value, the greater the wellbeing. The Y axis shows symptom intensity score by ReQuestÒ. The graph shows mean scores. ITT intention-totreat, PP per protocol

J. M. Remes-Troche et al.

(0.27 %, n = 14), nausea (0.18 %, n = 10), constipation (0.15 %, n = 8), dizziness (0.13 %, n = 7), and headache (0.13 %, n = 7).

4 Discussion In this large, multicentric, observational study we found that pantoprazole magnesium 40 mg once daily for 4 weeks is effective, safe, and well-tolerated in GERD patients. Furthermore, patients experienced a significant relief of both typical and atypical GERD symptoms, and this symptomatic relief was obtained during the first 7 days of treatment and sustained during the following weeks. Today, although the efficacy of PPIs with a once-daily dosing regimen is well-recognized and widely recommended, one-quarter to one-third of GERD patients remain symptomatic [25, 26]. Several factors are associated to PPI failure, some of them related to the patient (inappropriate taking of the dose or psychological co-morbidity) and others related to the drugs [25, 27]. For example, persistent symptoms may be in part because there is effectively no circulating PPI present at the end of the 24-h interval, which may lead to breakthrough symptoms, most notably nocturnal heartburn, which can be difficult to treat with the standard once-daily dosing of conventional PPIs [28]. In our study, at baseline up to 64 % of patients with GERD had sleep disturbances and one-third at least one of the extra-esophageal manifestations of GERD such as chronic cough or dyspnea.

Pantoprazole Magnesium in Symptomatic GERD

One of the strategies to increase PPI efficacy include use of magnesium formulations such as in esomeprazole, omeprazole or, more recently, pantoprazole [17]. Pantoprazole magnesium has a prolonged elimination half-life compared with pantoprazole sodium; these differences in their pharmacokinetic parameters are likely due to the slow dissolution of the magnesium-containing tablets in the stomach, resulting in reduced solubility which may result in longer gastric acid suppression for day-time and nighttime symptom control, as is shown in our study. In the study by Hein [17], pantoprazole magnesium was as effective as pantoprazole sodium for healing esophageal erosions at 8 weeks but better at 4 weeks. Also, in this study more patients experienced relief across a broad range of symptoms, like in our study. Because of the large sample size and the multicentric nature of our study, assessment of healing was very difficult. However, we decided to use symptomatic relief as our main goal based in the fact that up to 60 % of patients had non-erosive GERD and, most importantly, we wanted to show the effect of pantoprazole magnesium in a real-life setting. Also, it is important to remark that effectiveness was based on symptomatic relief using well-validated methods: severity of symptoms assessed by the physician and changes in the ReQuestÒ [21–23]. This provides independent scores for symptom severity changes. It is important to stress that there was no correlation between the symptom intensity assessed by physicians/investigators and that assessed by patients, and despite this lack of agreement, both assessing groups showed improvement in symptom severity. This fact reinforces that the use of pantoprazole 40 mg once daily significantly reduces symptom intensity. Using both the ReQuestÒ and physician assessments we found that the average improvement for symptom intensity ranged between 70 and 80 % for global assessment as well as for acid complaints, upper and lower abdominal symptoms, nausea, and sleep disturbances. It should be noted that using the ReQuestÒ, percentage changes in improvement of symptoms intensity were highest at the end of the first week; thus, it seems that pantoprazole magnesium provided a rapid but sustained effect for control of GERDrelated symptoms. These results are similar to those reported by Hein [17]. The high rates of early symptom relief observed with pantoprazole magnesium in the current study make it a good alternative to other PPIs for the successful management of GERD and important for maintaining patient satisfaction, especially when night-time symptoms are present [17, 29]. Our findings support that the waning of acid inhibition at night is due to the prolonged elimination halflife reported for pantoprazole magnesium.

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PPIs are widely used in clinical practice. However, recently several concerns have been expressed about their long-term use, particularly with regard to bone health, hypomagnesaemia, Clostridium difficile infections, and drug interactions with platelet aggregation inhibitors [18, 30–33]. Among all of the side effects and interaction of PPIs, the clopidrogel–PPI interaction is the more controversial and life-threatening. Rising evidence suggests that the bleeding reduction benefit outweighs the possible adverse cardiovascular risk in patients with an indication for PPI treatment taking dual antiplatelet treatment [30, 33]. However, in vitro and in vivo studies have provided direct evidence that PPIs inhibit clopidrogel metabolic activation and suggest that cytochrome P450 (CYP) 2C19 inhibition is the main cause of drug–drug interaction between clopidrogel and PPIs [32, 33]. Most retrospective cohort studies and studies using platelet markers found a significant association between PPI use, especially omeprazole, and decreased efficacy of clopidrogel, while few comparative trials using clinical outcomes found no association between the same [30–33]. Among all of the PPIs, pantoprazole is a weak inhibitor of CYP2C19 and has less effect on the pharmacological activity of clopidrogel than omeprazole, and has not been associated with a decrease in the antiplatelet efficacy of clopidrogel. Thus, pantoprazole is considered the safest PPI. In this study, we found that pantoprazole magnesium is a well-tolerated and safe drug, with no unexpected adverse drug reactions and a safety profile similar to that expected from preclinical data [17]. Also, given its pharmacodynamics and pharmacokinetic profile, its safety profile is similar to pantoprazole sodium. A definitive and likely causally related adverse effect was reported in 1.39 % of patients and these were those also reported with pantoprazole sodium and other PPIs: diarrhea, nausea, constipation, dizziness, and headache. Recently, hypomagnesemia has been reported in adult patients taking PPIs for at least 3 months, but most cases occurred after a year of treatment [30, 31]. No cases of hypomagnesemia have been reported in our database to date. A main limitation of our study was that in only 21 % of the cases was endoscopy performed according to the investigator criteria, thus a selection bias is obvious. However, as mentioned previously, our main goal was to assess the efficacy of pantoprazole magnesium in symptomatic GERD, and not the healing rates for erosive GERD. Also, even when endoscopy was not performed, the probability for structural disease in the absence of alarm signs in a cohort with a mean age of \50 years (mean age 37 years) is very low [34]. Another limitation of our study was the short duration of treatment, because an 8-week

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course of a PPI is the therapy of choice for symptom relief and healing of esophagitis [34].

5 Conclusion In this study we found that pantoprazole magnesium dehydrate 40 mg once daily for 4 weeks significantly improves GERD symptoms. The effectiveness was observed during the first 7 days and was sustained along the 4 weeks of treatment. Treatment effects were not restricted to acid complaints but occurred in all dimensions evaluated. We also found that pantoprazole magnesium is safe and well-tolerated in GERD patients. Acknowledgments The current study was sponsored by Nykomed, Mexico. Nykomed did not participate in the writing of this article or in the decision to submit the article for publication. Jose´ M. RemesTroche has received consultancy honoraria from Takeda, Janssen, and AstraZeneca. Antonio Orozco-Gamiz has worked as a speaker for Takeda, GlaxoSmithKline, and Bristol-Myers Squibb. Julio Ce´sar Soto-Pe´rez, Oscar Teramoto-Matsubara, Gualberto Mateos, Sergio Sobrino-Cossı´o, Miguel Morales-Ara´mbula, and Jose´ Luis Tamayo de la Cuesta have no conflicts of interest that are directly relevant to the content of this study.

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