Glenn Davies

Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy

ABSTRACT Objective: To review and analyse the evidence for the cholesterol-lowering effect of ezetimibe in adult patients with hypercholesterolaemia who are not at low-density lipoprotein cholesterol (LDL‑C) goal on statin monotherapy. Research design: Systematic review and meta-analysis. Methods: MEDLINE and EMBASE were searched to identify ezetimibe randomised controlled trials (RCTs) published between January 1993 and December 2005. The meta-analysis combined data from RCTs, with a minimum treatment duration of 6 weeks, that compared treatment with ezetimibe 10 mg/day or placebo added to current statin therapy. The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in total cholesterol (TC), LDL‑C, and high-density lipoprotein cholesterol (HDL‑C), and number of patients achieving LDL‑C treatment goal. Meta-analysis results are presented for a modified version of the inverse variance random effects model. Results: Five RCTs involving a total of 5039 patients were included in the meta-analysis. The weighted mean difference (WMD) between treatments significantly favoured the ezetimibe/statin combination over placebo/statin for TC (–16.1% (–17.3, –14.8); p < 0.0001), LDL‑C (–23.6% (–25.6, –21.7); p < 0.0001) and HDL‑C (1.7% (0.9, 2.5); p < 0.0001). The relative risk of reaching the LDL‑C treatment goal was significantly higher for patients on ezetimibe/statin relative to those on placebo/statin (3.4 (2.0, 5.6); p < 0.0001). In pre-defined sub-group analyses of studies in patients with coronary heart disease, the WMD between treatments remained significantly in favour of ezetimibe/statin ( p < 0.0001) for TC and LDL‑C but was no longer significant for HDL‑C. Elevations in creatine kinase, alanine aminotransferase or aspartate aminotransferase that were considered as an adverse effect did not differ significantly between treatments. Conclusions: The meta-analysis we performed included only five studies and was restricted to analysis of the changes in cholesterol levels relative to baseline. However, the results suggest that ezetimibe co-administered with ongoing statin therapy provides significant additional lipid-lowering in patients not at LDL‑C goal on statin therapy alone, allowing more patients to reach their LDL‑C goal.

Cholesterol reduction yields clinical benefits: meta-analysis including recent trials

BACKGROUND Previous meta-analyses reported by Gould et al found significant decreases of 15% in the risk for coronary heart disease (CHD)-related mortality and 11 % in risk for all-cause mortality per decrease of 10% in total cholesterol (TC) level. OBJECTIVE To evaluate the effects of reducing cholesterol on clinical events after including data from recent clinical trials. METHODS Using a literature search (MeSH key terms, including: bezafibrate, coronary disease, efficacy, gemfibrozil, hydroxymethylglutaryl-CoA reductase inhibitors, hypercholesterolemia, niacin [nicotinic acids], randomized controlled trials, and treatment outcome; years: 1999-2005), we identified trials published in English that assessed the effects of lipid-modifying therapies on CHD end points, including CHD-related death, myocardial infarction, and angina pectoris. We also included all studies from the previously published meta-analysis. Using the same analytic approach as previously, we determined the effects of net absolute reductions (1 mmol/L [38.7 mg/dL]) in TC and low-density lipoprotein cholesterol (LDL-C) on the relative risks (RRs) for all-cause mortality, CHD-related mortality, any CHD event (mortality or nonfatal myocardial infarction), and non-CHD-related mortality. RESULTS We included 62 studies involving 216,616 patients, including 126,474 from 24 randomized controlled trials the findings of which were published since the previous meta-analysis (1998). Among all patients, for every 1-mmol/L decrease in TC, there was a 17.5 reduction in RR for all-cause mortality; 24.5 %, for CHD-related mortality; and 29.5% for any CHD event. Corresponding reductions for every 1-mmol/L decrease in LDL-C were 15.6%, 28.0%, and 26.6%, respectively. Similar relationships were observed in patients without CHD. No significant relationship was found between lipid reduction and non-CHD-related mortality risk. CONCLUSIONS The results from the present analysis support conclusions from previous meta-analyses that cholesterol lowering is clinically beneficial in patients with CHD or at elevated CHD risk. These results also support the previous finding that non-CHD-related mortality is unrelated to lipid reductions.

Comparison of the responsiveness and relative effect size of the western Ontario and McMaster Universities Osteoarthritis Index and the short-form Medical Outcomes Study Survey in a randomized, clinical trial of osteoarthritis patients.

OBJECTIVE This study compares the responsiveness and relative effect sizes of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) with the Medical Outcomes Study Short Form Health Survey (SF-36) in a randomized clinical trial for treatment of osteoarthritis (OA). METHODS Patients with OA of the knee or hip were randomized to receive either placebo or 2,400 mg/day of ibuprofen for 28 days. Patients completed the WOMAC and SF-36 at baseline and days 7, 14, and 28 of the trial. RESULTS Patients receiving ibuprofen showed significant improvement in WOMAC pain, physical functioning, and the total score, while improvement was detected only for bodily pain on the SF-36. The WOMAC detected significant differences between ibuprofen and placebo for pain and physical functioning, whereas the SF-36 detected differences for the bodily pain subscale. CONCLUSION These results suggest the WOMAC has greater power to detect treatment differences than the SF-36, with respect to pain and physical functioning, in OA clinical trials.

Comparative efficacy of the addition of ezetimibe to statin vs statin titration in patients with hypercholesterolaemia: systematic review and meta-analysis

Abstract Objective: To systematically review and analyse evidence for cholesterol-lowering efficacy of at least 4 weeks of add-on ezetimibe vs doubling statin dose, in adults with primary hypercholesterolaemia. Research design and methods: MEDLINE, EMBASE and Cochrane databases were searched to identify randomised controlled trials of ezetimibe–statin combination vs statin titration (January 1993 – March 2010). Studies were selected using predefined criteria. Two reviewers conducted screening of articles, critical appraisal and data extraction; a third reviewer resolved disagreements. The difference between treatments was analysed for four co-primary outcomes: mean percentage change from baseline in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC); and proportion of patients achieving LDL-C treatment goal. Data were combined by two sets of direct comparison fixed and random effects meta-analysis: (1) compared data in the same treatment period between groups; (2) compared the incremental change in lipid levels of add-on ezetimibe vs doubling statin dose. Heterogeneity was assessed using the I2 statistic. Results: Thirteen studies including 5080 patients were included in the meta-analyses. Data on simvastatin, atorvastatin and rosuvastatin were analysed. Results for primary and secondary outcomes were in favour of the ezetimibe–statin combination. A significantly greater percentage reduction in LDL-C levels was achieved in patients treated with ezetimibe–statin vs statin monotherapy (weighted mean difference [WMD]: −14.1% [−16.1, −12.1], p < 0.001). Reduction in LDL-C levels attributed to add-on ezetimibe was significantly greater than that for statin dose doubling (WMD: −15.3% [−19.1, −11.4], p < 0.001). Achievement of LDL-C goal favoured add-on ezetimibe over statin titration and was statistically significant (odds ratio: LDL-C treatment goal 2.45 [1.95, 3.08], p = 0.007). Conclusions: Meta-analyses were restricted by the limited number of studies with similar trial design and method of statin titration. Results indicate that add-on ezetimibe is significantly more effective in reducing LDL-C levels than doubling statin dose, enabling more patients to achieve LDL-C goal.

Validation of an asthma symptom diary for interventional studies

OBJECTIVE The Pediatric Asthma Diary was developed and validated to assess efficacy of interventions in children with asthma. DESIGN, PATIENTS, AND SETTING Diary validation was performed in a three week, prospective study of 106 children aged 6–14 years with asthma. Children were classified at baseline as either stable (requiring no additional asthma treatment) or new onset/worse (requiring either addition of or increase in anti-inflammatory treatment). RESULTS A daytime symptom scale and “day without asthma” were defined from diary questions. Both measures demonstrated significant validity and responsiveness to anti-inflammatory treatment. The stable group experienced a higher percentage of days without asthma during week 1 compared with the new onset/worse group (39.6%v 11.6%, respectively). The new onset/worse patients experienced significant improvement in days without asthma (24.5%) compared with stable patients (6.4%). CONCLUSIONS The Pediatric Asthma Diary daytime symptom scale and day without asthma are acceptable measures for use in asthma intervention studies of children aged 6–14 years.

Determinants of migraine-specific quality of life

This paper reports an analysis of two randomized controlled trials of rizatriptan, in which the 24-h Migraine Quality of Life Questionnaire© was used to assess migraine-specific quality of life in patients receiving acute treatment. The objective of the analysis was to determine which clinical effects of a migraine medication, as measured by traditional clinical trial endpoints, contribute to a better short-term health-related quality of life. The results demonstrate that patients who experience complete pain relief and are able to function at their normal ability within 2 h and experience no headache recurrence have the highest migraine-specific quality of life scores. Patients who were satisfied with medication at 2 h had higher migraine-specific quality of life scores than those who were not satisfied. In conclusion, migraine therapy that provides rapid, complete, and sustained pain relief, with restoration of functional ability, has the most beneficial impact on short-term health-related quality of life for migraineurs.

The role of ezetimibe in LDL cholesterol goal attainment in very high risk patients

Address for correspondence: D. P. Mikhailidis, MD, FFPM, FRCP, FRCPath, Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital Campus, University College London (UCL) Medical School, UCL, London, NW3 2QG, UK. Tel.: þ44 (0) 20 783