Randomised clinical trial: The ileal bile acid transporter inhibitor A3309 vs. placebo in patients with chronic idiopathic constipation--a double-blind study

Aliment Pharmacol Ther 2011; 34: 41–50

Summary

Background  One half of patients with constipation are not satisfied with available therapies, hence there is a need for more effective and well‐tolerated drugs. Aim  To evaluate the effects of a specific inhibitor of the Ileal Bile Acid Transporter (IBAT; syn apical sodium‐dependent bile acid transporter; ASBT) in patients with chronic idiopathic constipation (CIC) with focus on safety, colonic transit and efficacy signals. Methods  This was a single‐centre, prospective, randomised, double‐blind, placebo‐controlled study with a dose‐escalating design in patients with CIC. In addition to evaluation of conventional safety and tolerability parameters, (i) colonic transit time (CTT) was measured using radio‐opaque markers, (ii) metabolic parameters [lipid profile, C4 (7α‐hydroxy‐4‐cholesten‐3‐one) and FGF19 (Fibroblast Growth Factor 19)] were evaluated, and (iii) constipation parameters, such as changes in stool frequency and consistency, were analysed. Results  Thirty patients were randomised into five dose‐levels (range: 0.1–10 mg/day) or to placebo. All patients completed a 14‐day treatment period, and the safety/tolerability analysis was favourable. A3309, present in picomolar concentrations in plasma, induced up to a three‐fold increase in bile acid synthesis (C4) and a reduction of plasma FGF19, as well as reduction in total and LDL cholesterol. CTT was reduced in the highest dose groups; the main acceleration was identified in the left colon. Efficacy parameters showed trends for increased number of spontaneous bowel movements and improved stool consistency. Conclusions  Ileal Bile Acid Transporter inhibition is a novel mechanism for treatment of patients with chronic idiopathic constipation and has additional benefits of improving metabolic parameters (EudraCT 2008‐003255 ‐ 72).     

Impact of Periprocedural Myocardial Biomarker Elevation on Mortality Following Elective Percutaneous Coronary Intervention

ObjectivesThis study sought to explore the association between biomarker elevation, with creatine kinase–myocardial band (CK-MB) or cardiac troponin (cTn), following percutaneous coronary intervention (PCI) and mortality in patients undergoing PCI for stable angina with normal baseline values.BackgroundSeveral studies have shown a strong association between post-PCI CK-MB elevation and subsequent mortality. However, the prognostic significance of troponin elevation following coronary intervention is still debated.MethodsPatient-level data from 5 contemporary coronary stent trials and 1 large registry were pooled. Mortality of patients with stable angina, with normal baseline biomarkers, was compared between patients with and those without different cutoff values of cTn and CK-MB.ResultsA total of 13,452 patients were included in this pooled analysis. The overall percentage of patients with elevated biomarkers following PCI was 23.9% for CK-MB and 68.4% for cTn. In the patient cohort for whom both assays were available (n = 8,859), 2.4% had both CK-MB ≥5 × the upper limit of normal (ULN) and cTn ≥35 × ULN, while 92% had both CK-MB <5 × ULN and cTn <35 × ULN. Among patients with CK-MB ≥5 × ULN (n = 315), 212 (67.3%) also had cTn ≥35 × ULN. Conversely, 390 of patients (64.8%) who had cTn ≥35 × ULN did not have CK-MB ≥5 × ULN. A total of 259 patients (1.9%) died at 1 year; 20 (7.7%) had CK-MB ≥5 × ULN, and 23 (8.8%) had cTn ≥35 × ULN. In the Cox multivariate analysis, in which the CK-MB and cTn ratios post-procedure were forced into the model, age, prior myocardial infarction, lesion complexity, hyperlipidemia, and CK-MB ratio (≥10) post-procedure were associated with increased 1-year mortality.ConclusionsFollowing elective PCI in patients in stable condition treated with second-generation drug-eluting stent, CK-MB and cTn elevations remain common. After multivariate adjustment, there was an increased mortality rate with elevation of CK-MB after PCI, whereas cTn elevation was not independently associated with mortality at 1 year.     

A transient ischaemic attack clinic with round-the-clock access (SOS-TIA): feasibility and effects

BACKGROUND: Diagnosis and treatment of cerebral and retinal transient ischaemic attacks (TIAs) are often delayed by the lack of immediate access to a dedicated TIA clinic. We evaluated the effects of rapid assessment of patients with TIA on clinical decision making, length of hospital stay, and subsequent stroke rates. METHODS: We set up SOS-TIA, a hospital clinic with 24-h access. Patients were admitted if they had sudden retinal or cerebral focal symptoms judged to relate to ischaemia and if they made a total recovery. Assessment, which included neurological, arterial, and cardiac imaging, was within 4 h of admission. A leaflet about TIA with a toll-free telephone number for SOS-TIA was sent to 15 000 family doctors, cardiologists, neurologists, and ophthalmologists in Paris and its administrative region. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death within 1 year. FINDINGS: Between January, 2003, and December, 2005, we admitted 1085 patients with suspected TIA; 574 (53%) were seen within 24 h of symptom onset. 701 (65%) patients had confirmed TIA or minor stroke, and 144 (13%) had possible TIA. 108 (17%) of the 643 patients with confirmed TIA had brain tissue damage. Median duration of symptoms was 15 min (IQR 5-75 min). Of the patients with confirmed or possible TIA, all started a stroke prevention programme, 43 (5%) had urgent carotid revascularisation, and 44 (5%) were treated for atrial fibrillation with anticoagulants. 808 (74%) of all patients seen were sent home on the same day. The 90-day stroke rate was 1.24% (95% CI 0.72-2.12), whereas the rate predicted from ABCD(2) scores was 5.96%. INTERPRETATION: Use of TIA clinics with 24-h access and immediate initiation of preventive treatment might greatly reduce length of hospital stay and risk of stroke compared with expected risk.     

Drug Treatment and Cost of Cardiovascular Disease in Australia

Australia's Pharmaceutical Benefits Scheme supports the use of effective drugs for the prevention and control of cardiovascular risk factors. However, there are little data available describing per person costs of medication in primary prevention and secondary prevention in the community. We aim to understand annual expenditure on cardiovascular medicines according to the level and extent of cardiovascular disease, using participants enrolled in the Reduction of Atherothrombosis for Continued Health (REACH) registry. 2873 participants were recruited into the REACH registry through 273 Australian general practices. Cardiovascular medicines review was undertaken at baseline. Average weighted costs of medications were estimated using government‐reimbursed prices. Annual costs were stratified by disease extent and location. The annual mean cost of pharmaceuticals per person was AU$1307. The average reported medicine use per person across all states and participants groups varied significantly. Participants with cerebrovascular or peripheral arterial disease were prescribed less cardiovascular medication than those with coronary artery disease (CAD) (mean number of drugs 3.5 vs. 4.5, P < 0.0001) and (3.6 vs. 4.5, P < 0.0001), while those with risk factor alone had the same medication use as those with CAD (mean number 4.5). Medication use was lower in Western Australia in comparison to eastern States. Participants with existing cerebrovascular disease and peripheral vascular disease receive less preventive therapy than those with CAD or even risk factors alone. This observation is consistent across all mainland states. Given the evidence of the effectiveness and cost‐effectiveness of treating all types of vascular diseases, the present study suggests that there is scope to improve the treatment of these high‐risk participants in Australia.