ObjectivesWe conducted a systematic literature review to assess the adverse event (AE) profile of paracetamol.MethodsWe searched Medline and Embase from database inception to 1 May 2013. We screened for observational studies in English, which reported mortality, cardiovascular, gastrointestinal (GI) or renal AEs in the general adult population at standard analgesic doses of paracetamol. Study quality was assessed using Grading of Recommendations Assessment, Development and Evaluation. Pooled or adjusted summary statistics were presented for each outcome.ResultsOf 1888 studies retrieved, 8 met inclusion criteria, and all were cohort studies. Comparing paracetamol use versus no use, of two studies reporting mortality one showed a dose–response and reported an increased relative rate of mortality from 0.95 (0.92 to 0.98) to 1.63 (1.58 to 1.68). Of four studies reporting cardiovascular AEs, all showed a dose–response with one reporting an increased risk ratio of all cardiovascular AEs from 1.19 (0.81 to 1.75) to 1.68 (1.10 to 2.57). One study reporting GI AEs reported a dose–response with increased relative rate of GI AEs or bleeds from 1.11 (1.04 to 1.18) to 1.49 (1.34 to 1.66). Of four studies reporting renal AEs, three reported a dose–response with one reporting an increasing OR of ≥30% decrease in estimated glomerular filtration rate from 1.40 (0.79 to 2.48) to 2.19 (1.4 to 3.43).DiscussionGiven the observational nature of the data, channelling bias may have had an important impact. However, the dose–response seen for most endpoints suggests a considerable degree of paracetamol toxicity especially at the upper end of standard analgesic doses.

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Searching primary care databases for people at high risk of FH followed by cascade testing is likely to be cost-effective.

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Background and aims:The cost effectiveness of cascade testing for familial hypercholesterolaemia (FH) is well recognised. Less clear is the cost effectiveness of FH screening when it includes case identification strategies that incorporate routinely available data from primary and secondary care electronic health records.Methods: Nine strategies were compared, all using cascade testing in combination with different index case approaches (primary care identification, secondary care identification, and clinical assessment using the Simon Broome (SB) or Dutch Lipid Clinic Network (DLCN) criteria). A decision analytic model was informed by three systematic literature reviews and expert advice provided by a NICE Guideline Committee. Results:The model found that the addition of primary care case identification by database search for patients with recorded total cholesterol >9.3 mmol/L was more cost effective than cascade testing alone. The incremental cost-effectiveness ratio (ICER) of clinical assessment using the DLCN criteria was £3,254 per quality-adjusted life year (QALY) compared with case-finding with no genetic testing.The ICER of clinical assessment using the SB criteria was £13,365 per QALY (compared with primary care identification using the DLCN criteria), indicating that the SB criteria was preferred because it achieved additional health benefits at an acceptable cost. Secondary care identification with either the SB or DLCN criteria, was not cost effective, alone (dominated and dominated respectively) or combined with primary care identification (£63, 514 per QALY, and £82,388 per QALY respectively).Conclusions: Searching primary care databases for people at high risk of FH followed by cascade testing is likely to be cost-effective.