Lis Ohlsson

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

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.

The Influence of Renal Function on Clinical Outcome and Response to β-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.

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.

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‐methylglutaryl‐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

SUMMARY 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 1.6μmol-h/l_ (ratio 1.01 for treatment II/I and 0.97 for treatment III/I), the mean peak concentration (Cmax) was 0.3μmol/L (ratio 1.04 for treatment II/I and 1.02 for treatment III/I) and the mean half-life (t1/2) was 2.8 h for all treatments. The time to Cmax (tmax) was 2.2 h 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 Cmax) 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 (Cmax) 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.

No clinically significant interactions between the oral direct thrombin inhibitor ximelagatran and amiodarone, atorvastatin, or digoxin

The oral direct thrombin inhibitor ximelagatran has shown clinical benefit in patients with atrial fibrillation at risk of stroke. The potential for interaction of ximelagatran with amiodarone, atorvastatin, or digoxin, was assessed in 3 randomized studies in healthy volunteers. Methods: Study 1 was a placebo‐controlled, parallel‐group study (n=26) with ximelagatran (36mg) or placebo BID for 8 days and amiodarone (single 600mg oral dose) on Day 4. Study 2 was a crossover study (n=16) with atorvastatin (single 40mg oral dose) during one treatment period and ximelagatran (36mg BID for 5 days) plus a single dose of atorvastatin (40mg) on Day 4 during the other treatment period. Study 3 was a double‐blind, crossover study (n=16) with ximelagatran (36mg) or placebo BID for 8 days and digoxin (single 0.5mg dose) on Day 4. Results: For melagatran, the active form of ximelagatran, AUC and Cmax geometric mean ratios (90% CI) for combined therapy relative to monotherapy with either drug were within or only slightly outside predefined bounds for no interaction. Similarly, no relevant changes were observed for the AUC and Cmax of amiodarone, atorvastatin, or digoxin. None of the coadministered drugs affected the concentration–effect relationship of melagatran on activated partial thromboplastin time. Conclusions: No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when ximelagatran was administered with amiodarone, atorvastatin, or digoxin.

Effect of erythromycin on the pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran and its active form melagatran

Ximelagatran (Exanta™, AstraZeneca), an oral direct thrombin inhibitor for the prevention and treatment of thromboembolic disorders, is rapidly absorbed and bioconverted to its active form melagatran. The metabolism of ximelagatran is independent of CYP450 enzymes and hence it has a low potential for drug interactions. This study evaluated the effect of erythromycin on the pharmacokinetics (PK) and pharmacodynamics (PD) of melagatran. Methods: An open, sequential, single‐centre study in healthy volunteers (n=16; mean age 24 years, range 20–32 years) with ximelagatran 36mg on Day 1, then erythromycin 500mg TID on Days 2–5 followed by ximelagatran 36 mg plus erythromycin on Day 6. Results: For melagatran, AUC and Cmax geometric mean ratios for combined therapy (Day 6) relative to monotherapy (Day 1) were 1.82 (90% CI, 1.64–2.01) and 1.74 (90% CI, 1.52–2.00), respectively, (n=15), falling outside of the predefined bounds for no interaction. Geometric mean ratios for tmax and t1/2 of melagatran were 1.14 and 0.93, respectively. The erythromycin‐associated elevation in plasma melagatran concentrations increased the peak activated partial thromboplastin time (aPTT) prolongation from 41s to 44s. Ximelagatran was well tolerated alone, and in combination with erythromycin. Conclusions: This study showed evidence of a pharmacokinetic interaction between ximelagatran and erythromycin with respect to melagatran PK, which is being investigated, but only a small effect on aPTT.

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.

The pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor ximelagatran when administered with azithromycin and cefuroxime

Ximelagatran is bioconverted to its active form melagatran. It has a low potential for drug interactions as its metabolism is independent of CYP450 enzymes.