Prevalence of gastro-oesophageal reflux disease with upper gastrointestinal symptoms without heartburn and regurgitation.

BACKGROUND: Symptomatically 'silent' gastro-oesophageal reflux disease (GORD) may be underdiagnosed. OBJECTIVE: To determine the prevalence of untreated GORD without heartburn and/or regurgitation in primary care. METHODS: Patients were included if they had frequent upper gastrointestinal symptoms and had not taken a proton pump inhibitor in the previous 2 months (Diamond study: NCT00291746). GORD was diagnosed based on the presence of reflux oesophagitis, pathological oesophageal acid exposure, and/or a positive symptom-acid association probability. Patients completed the Reflux Disease Questionnaire (RDQ) and were interviewed by physicians using a prespecified symptom checklist. RESULTS: GORD was diagnosed in 197 of 336 patients investigated. Heartburn and/or regurgitation were reported in 84.3% of patients with GORD during the physician interviews and in 93.4% of patients with GORD when using the RDQ. Of patients with heartburn and/or regurgitation not identified at physician interview, 58.1% (18/31) reported them at a 'troublesome' frequency and severity on the RDQ. Nine patients with GORD did not report heartburn or regurgitation either at interview or on the RDQ. CONCLUSIONS: Structured patient-completed questionnaires may help to identify patients with GORD not identified during physician interview. In a small proportion of consulting patients, heartburn and regurgitation may not be present in those with GORD.

Symptom overlap between postprandial distress and epigastric pain syndromes of the Rome III dyspepsia classification.

OBJECTIVES: The Rome III criteria for functional dyspepsia recognize two distinct subgroups: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). The aim of this exploratory analysis was to evaluate the Rome III criteria and the validity of the PDS/EPS subgrouping in primary care patients with upper gastrointestinal symptoms. METHODS: Primary care patients with frequent upper gastrointestinal symptoms included in the Diamond study (NCT00291746) underwent esophageal endoscopy and 24-h pH-metry. Gastroesophageal reflux disease (GERD) was defined as the presence of at least one of the following: reflux esophagitis, pathological esophageal acid exposure, positive symptom association probability (SAP ≥95%) for association of symptoms with acid reflux. Functional dyspepsia was defined by the absence of GERD and peptic ulcer disease on investigation. PDS and/or EPS were diagnosed according to Rome III criteria. RESULTS: In total, 138 patients (41%) had upper gastrointestinal symptoms with normal endoscopy, pH-metry, and SAP results, consistent with the presence of functional dyspepsia. Of these patients, 130 (94%) met criteria for PDS and/or EPS: 13 (10%) had PDS alone, 31 (24%) had EPS alone, and 86 (66%) met criteria for both PDS and EPS. CONCLUSIONS: PDS and EPS overlap in the majority of patients with functional dyspepsia. The value of dividing functional dyspepsia into the subgroups of PDS and EPS is thus questionable. A new approach to classifying functional dyspepsia is needed.

The influence of renal function on clinical outcome and response to beta-blockade in systolic heart failure: insights from Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF).

BACKGROUND: Limited information is available on the risk and impact of renal dysfunction on the response to beta-blockade and mode of death in systolic heart failure (HF). METHODS AND RESULTS: Renal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR(MDRD) > 60 (n = 2496), eGFR(MDRD) 45 to 60 (n = 976), and eGFR(MDRD) < 45 mL/min per 1.73 m(2) body surface area (n = 493). Hazard ratio (HR) was estimated with Cox proportional hazards models adjusted for prespecified risk factors. Placebo patients with eGFR < 45 had significantly higher risk than those with eGFR > 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR < 45 and eGFR > 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR < 45. For total mortality, metoprolol CR/XL vs placebo: HR, 0.41 (95% CI. 0.25 to 0.68; P < .001) in those with eGFR < 45 compared with HR, 0.71 (95% CI, 0.54 to 0.95; P < .021) for those with eGFR > 60; corresponding data for the combined end point was HR, 0.44 (95% CI, 0.31 to 0.63; P < .0001) and HR, 0.75 (0.62 to 0.92; P = .005, respectively; P = .095 for interaction by treatment for total mortality; P = .011 for combined end point). Metoprolol CR/XL was well tolerated in all 3 renal function subgroups. CONCLUSIONS: Renal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR < 45 as in those with eGFR > 60.

Pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran co-administered with different classes of antibiotics in healthy volunteers.

OBJECTIVE: To study the effects of amoxicillin, doxycycline, ciprofloxacin, azithromycin, and cefuroxime on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, which is a substrate for the P-glycoprotein pump (P-gp) transporter but is not metabolized by the cytochrome P450 (CYP450) enzyme system. METHODS: Five parallel groups of 16 healthy volunteers received two sequential treatments. The first treatment was a single 36-mg dose of ximelagatran. During the second treatment period, one of the above antibiotics was given on days 1-5 after a washout of at least 2 days. A single 36-mg oral dose of ximelagatran was given on the mornings of days 1 and 5 of the second treatment period. RESULTS: No pharmacokinetic interactions were detected between ximelagatran and amoxicillin, doxycycline, or ciprofloxacin as the least-squares geometric mean treatment ratio of ximelagatran with-to-without antibiotic fell within the intervals of 0.80-1.25 for the area under the curve (AUC) and 0.7-1.43 for C(max). After co-administration with azithromycin, the least square mean ratio with-to-without antibiotic for AUC of melagatran was 1.60 (90% CI, 1.40-1.82) on day 1 and 1.41 (90% CI, 1.24-1.61) on day 5. For melagatran C(max), the corresponding ratios were 1.63 (90% CI, 1.38-1.92) and 1.40 (90% CI, 1.18-1.66). After co-administration with cefuroxime, the ratios were 1.23 (90% CI, 1.07-1.42) and 1.16 (90% CI, 0.972-1.38) for AUC and 1.33 (90% CI, 1.07-1.66) and 1.19 (90%CI, 0.888-1.58) for C(max) of melagatran. Co-administration with the antibiotics did not change mean time to C(max), half-life, or renal clearance of melagatran. The melagatran plasma concentration-response relationship for activated partial thromboplastin time (APTT) prolongation was not altered by any of the studied antibiotics, but the increased plasma concentrations of melagatran after co-administration of ximelagatran with azithromycin resulted in a minor increase in the mean maximum APTT of about 15%. CONCLUSION: The pharmacokinetics of ximelagatran were not affected by amoxicillin, doxycycline, or ciprofloxacin. Melagatran exposure was increased when ximelagatran was co-administered with azithromycin and, to a lesser extent, with cefuroxime. APTT was not significantly altered by any of the antibiotics.

Presence and development of atrial fibrillation in chronic heart failure. Experiences from the MERIT-HF Study.

BACKGROUND: Atrial fibrillation is common in heart failure, but data regarding beta-blockade in these patients and its ability to prevent new occurrence of atrial fibrillation are scarce. METHODS: Baseline ECGs in MERIT-HF were coded regarding baseline rhythm, and outcome was analyzed in relation to rhythm. Occurrence of atrial fibrillation during follow-up was also analyzed. RESULTS: At baseline atrial fibrillation was diagnosed in 556 patients (13.9%). Mean metoprolol CR/XL dose in patients in atrial fibrillation (154 mg) and sinus rhythm (158 mg) was similar, as well as decrease in heart rate (14.8 and 13.7 bpm, respectively). Only 61 (total of 362) deaths occurred in those in atrial fibrillation at baseline, 31 on placebo and 30 on metoprolol (RR 1.0; 95% CI 0.61-1.65). During follow-up, new atrial fibrillation was observed in 85 patients on placebo and 47 patients on metoprolol (RR 0.53; 95% CI 0.37-0.76; p=0.0005). CONCLUSION: First, given the wide confidence interval, it was impossible to detect an interaction between metoprolol and mortality in patients with atrial fibrillation and heart failure. Second, in patients with sinus rhythm at baseline, metoprolol reduced the incidence of atrial fibrillation during follow-up. However, we must be extremely cautious in over-interpreting effects in these subgroups.

No effect of encapsulation on the pharmacokinetics of warfarin.

BACKGROUND: In double-blind comparator studies with the oral direct thrombin inhibitor (oral DTI) ximelagatran, warfarin (Coumadin) was administered in encapsulated form in order to maintain patient and investigator blinding. This open, randomized, two-way crossover study was conducted to determine whether the encapsulated warfarin tablets (Coumadin) used in the ximelagatran studies are bioequivalent to nonencapsulated, commercially available warfarin (Coumadin) tablets. METHODS AND RESULTS: Eighteen healthy men received two 2.5 mg tablets of encapsulated warfarin and two 2.5 mg tablets of nonencapsulated warfarin as single oral doses, 14 days apart. The 90% confidence intervals for the mean treatment ratio (encapsulated tablet/nonencapsulated tablet) fell within the limits considered to reflect bioequivalence (0.80, 1.25) for total area under the plasma concentration-versus-time curve (AUC(infinity)), AUC to the last evaluable concentration (AUC(t)), and maximum plasma concentration (C(max)) for both R-warfarin (AUC(infinity) [0.93, 1.03], AUC(t) [0.95, 1.03], C(max) [0.90, 1.04]) and S-warfarin (AUC(infinity) [0.93, 1.03], AUC(t) [0.94, 1.03], C(max) [0.90, 1.06]). CONCLUSIONS: The encapsulated form of warfarin (Coumadin) used in comparator studies with the oral DTI ximelagatran is bioequivalent to the nonencapsulated, commercially available form of warfarin (Coumadin). Thus, the results of ximelagatran clinical trials with encapsulated warfarin can be generalized to the commercially available form.

No influence of food on the pharmacokinetics, pharmacodynamics or tolerability of the 24mg and 36mg oral tablet formulations of ximelagatran.

OBJECTIVE: To assess the potential effects of food on the pharmacokinetics and tolerability/safety of ximelagatran, an oral direct thrombin inhibitor developed for the prevention and treatment of thromboembolic disease that is rapidly bioconverted to its active form, melagatran. DESIGN AND STUDY PARTICIPANTS: In two open-label, randomised, crossover studies, healthy male and female volunteers received oral ximelagatran as a single 24mg tablet (study 1, n = 30) or a single 36mg tablet (study 2, n = 50). Potential effects of food on the pharmacodynamics (activated partial thromboplastin time; APTT) of the 36mg tablet were also investigated in study 2. RESULTS: For the 24mg tablet, the 90% confidence intervals (CIs) and least-squares mean estimates for the ratio of the tablet with food to the tablet without food fell within the predefined bounds demonstrating no effect on area under the melagatran concentration-time curve (AUC ratio = 0.94 [90% CI 0.90, 0.99]) or maximum plasma concentration (C(max) ratio = 0.88 [90% CI 0.82, 0.95]). The same result was observed for the 36mg tablet (AUC ratio = 1.07 [90% CI 1.03, 1.12]; C(max) ratio = 1.05 [90% CI 0.98, 1.12]). Melagatran AUC normalised for differences in bodyweight was comparable between women and men administered the 24mg or 36mg tablet without food. In addition, food did not clinically significantly alter the melagatran-induced prolongation of the APTT of the 36mg tablet. Ximelagatran was well tolerated with or without food. CONCLUSION: The pharmacokinetics (AUC, C(max)), pharmacodynamics (APTT) and tolerability of melagatran after administration of oral ximelagatran tablets were not affected by food.

No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran.

In this randomized, 2-way crossover study, the potential for interaction was investigated between atorvastatin and ximelagatran, an oral direct thrombin inhibitor. Healthy female and male volunteers (n = 16) received atorvastatin 40 mg as a single oral dose and, in a separate study period, ximelagatran 36 mg twice daily for 5 days plus a 40-mg oral dose of atorvastatin on the morning of day 4. In the 15 subjects completing the study, no pharmacokinetic interaction was detected between atorvastatin and ximelagatran for all parameters investigated, including melagatran (the active form of ximelagatran) area under the plasma concentration versus time curve (AUC) and maximum plasma concentration, atorvastatin acid AUC, and AUC of active 3-hydroxy-3-methyl-glutaryl-coenzyme-A (HMG-CoA) reductase inhibitors. Atorvastatin did not alter the melagatran-induced prolongation of the activated partial thromboplastin time, and both drugs were well tolerated when administered in combination. In conclusion, no pharmacokinetic or pharmacodynamic interaction between atorvastatin and ximelagatran was observed in this study.

Bioequivalence of ximelagatran, an oral direct thrombin inhibitor, as whole or crushed tablets or dissolved formulation.

OBJECTIVE: To investigate whether crushed or dissolved tablets of the oral direct thrombin inhibitor ximelagatran are bioequivalent to whole tablet administration. Ximelagatran is currently under development for the prevention and treatment of thromboembolic disorders. RESEARCH DESIGN AND METHODS: This was an open-label, randomised, three-period, three-treatment crossover study in which 40 healthy volunteers (aged 20-33 years) received a single 36-mg dose of ximelagatran administered in three different ways: I swallowed whole, II crushed, mixed with applesauce and ingested and III dissolved in water and administered via nasogastric tube. RESULTS: The plasma concentrations of ximelagatran, its intermediates and the active form melagatran were determined. Ximelagatran was rapidly absorbed and the bioavailability of melagatran was similar after the three different administrations, fulfilling the criteria for bioequivalence. The mean area under the plasma concentration-versus-time curve (AUC) of melagatran was 1.6 micromol.h/L (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (C(max)) was 0.3 micromol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t(1/2)) was 2.8 h for all treatments. The time to C(max) (t(max)) was 2.2h for the whole tablet and approximately 0.5 h earlier when the tablet was crushed or dissolved (1.7-1.8 h), due to a more rapid absorption. The study drug was well tolerated as judged from the low incidence and type of adverse events reported. CONCLUSION: The present study showed that the pharmacokinetics (AUC and C(max)) of melagatran were not significantly altered whether ximelagatran was given orally as a crushed tablet mixed with applesauce or dissolved in water and given via nasogastric tube.

Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men.

The pharmacokinetic dose linearity and reproducibility, the effects on ex-vivo coagulation time assays and bleeding time, and tolerability of the direct thrombin inhibitor melagatran following subcutaneous (s.c.) dosing were investigated in two open-label studies in healthy males: (i). a dose-escalation study in which subjects received single s.c. doses of melagatran (0.1-5 mg); and (ii). a repeated-dosing study in which 3 mg s.c. melagatran was administered at 12-h intervals for 4 days. In both studies, melagatran was rapidly absorbed with maximum plasma concentrations (C(max)) observed about 0.5 h post dosing. The half-life of melagatran was about 2 h. The area under the melagatran plasma concentration versus time curve increased linearly with dose. No time dependency in the area under the curve or Cmax was observed over 4 days of twice-daily dosing. The variability in pharmacokinetic parameters was low and the bioavailability of melagatran appeared to be complete. There was a steep and linear prolongation of thrombin time, a non-linear prolongation of both activated partial thromboplastin time and activated coagulation time, and a decrease in prothrombin complex activity with increasing melagatran plasma concentration. Only moderate increases in capillary bleeding time were observed with s.c. doses up to 5 mg melagatran. Melagatran was well tolerated after s.c. injection, with good local tolerability at the injection site.