Igho Onakpoya

Oseltamivir for influenza in adults and children: Systematic review of clinical study reports and summary of regulatory comments

Objective To describe the potential benefits and harms of oseltamivir by reviewing all clinical study reports (or similar document when no clinical study report exists) of randomised placebo controlled trials and regulatory comments (“regulatory information”). Design Systematic review of regulatory information. Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. Eligibility criteria for selecting studies Randomised placebo controlled trials on adults and children who had confirmed or suspected exposure to natural influenza. Main outcome measures Time to first alleviation of symptoms, influenza outcomes, complications, admissions to hospital, and adverse events in the intention to treat population. Results From the European Medicines Agency and Roche, we obtained clinical study reports for 83 trials. We included 23 trials in stage 1 (reliability and completeness screen) and 20 in stage 2 (formal analysis). In treatment trials on adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval 8.4 to 25.1 hours, P<0.001). There was no effect in children with asthma, but there was an effect in otherwise healthy children (mean difference 29 hours, 95% confidence interval 12 to 47 hours, P=0.001). In treatment trials there was no difference in admissions to hospital in adults (risk difference 0.15%, 95% confidence interval −0.91% to 0.78%, P=0.84) and sparse data in children and for prophylaxis. In adult treatment trials, oseltamivir reduced investigator mediated unverified pneumonia (risk difference 1.00%, 0.22% to 1.49%; number needed to treat to benefit (NNTB) 100, 95% confidence interval 67 to 451). The effect was not statistically significant in the five trials that used a more detailed diagnostic form for “pneumonia,” and no clinical study reports reported laboratory or diagnostic confirmation of “pneumonia.” The effect on unverified pneumonia in children and for prophylaxis was not significant. There was no significant reduction in risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. 14 of 20 trials prompted participants to self report all secondary illnesses to an investigator. Oseltamivir in the treatment of adults increased the risk of nausea (risk difference 3.66%, 0.90% to 7.39%; number needed to treat to harm (NNTH) 28, 95% confidence interval 14 to 112) and vomiting (4.56%, 2.39% to 7.58%; 22, 14 to 42). In treatment of children, oseltamivir induced vomiting (5.34%, 1.75% to 10.29%; 19, 10 to 57). In prophylaxis trials, oseltamivir reduced symptomatic influenza in participants by 55% (3.05%, 1.83% to 3.88%; NNTB 33, 26 to 55) and households (13.6%, 9.52% to 15.47%; NNTB 7, 6 to 11) based on one study, but there was no significant effect on asymptomatic influenza and no evidence of a reduction in transmission. In prophylaxis studies, oseltamivir increased the risk of psychiatric adverse events during the combined “on-treatment” and “off-treatment” periods (risk difference 1.06%, 0.07% to 2.76%; NNTH 94, 36 to 1538) and there was a dose-response effect on psychiatric events in two “pivotal” treatment trials of oseltamivir, at 75 mg (standard dose) and 150 mg (high dose) twice daily (P=0.038). In prophylaxis studies, oseltamivir increased the risk of headaches on-treatment (risk difference 3.15%, 0.88% to 5.78%; NNTH 32, 18 to 115), renal events with treatment (0.67%, −0.01% to 2.93%), and nausea while receiving treatment (4.15%, 0.86% to 9.51%; NNTH 25, 11 to 116). Conclusions In prophylactic studies oseltamivir reduces the proportion of symptomatic influenza. In treatment studies it also modestly reduces the time to first alleviation of symptoms, but it causes nausea and vomiting and increases the risk of headaches and renal and psychiatric syndromes. The evidence of clinically significant effects on complications and viral transmission is limited because of rarity of such events and problems with study design. The trade-off between benefits and harms should be borne in mind when making decisions to use oseltamivir for treatment, prophylaxis, or stockpiling.

Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature

BackgroundThere have been no studies of the patterns of post-marketing withdrawals of medicinal products to which adverse reactions have been attributed. We identified medicinal products that were withdrawn because of adverse drug reactions, examined the evidence to support such withdrawals, and explored the pattern of withdrawals across countries.MethodsWe searched PubMed, Google Scholar, the WHO’s database of drugs, the websites of drug regulatory authorities, and textbooks. We included medicinal products withdrawn between 1950 and 2014 and assessed the levels of evidence used in making withdrawal decisions using the criteria of the Oxford Centre for Evidence Based Medicine.ResultsWe identified 462 medicinal products that were withdrawn from the market between 1953 and 2013, the most common reason being hepatotoxicity. The supporting evidence in 72 % of cases consisted of anecdotal reports. Only 43 (9.34 %) drugs were withdrawn worldwide and 179 (39 %) were withdrawn in one country only. Withdrawal was significantly less likely in Africa than in other continents (Europe, the Americas, Asia, and Australasia and Oceania). The median interval between the first reported adverse reaction and the year of first withdrawal was 6 years (IQR, 1–15) and the interval did not consistently shorten over time.ConclusionThere are discrepancies in the patterns of withdrawal of medicinal products from the market when adverse reactions are suspected, and withdrawals are inconsistent across countries. Greater co-ordination among drug regulatory authorities and increased transparency in reporting suspected adverse drug reactions would help improve current decision-making processes.

The effect of green tea on blood pressure and lipid profile: a systematic review and meta-analysis of randomized clinical trials.

INTRODUCTION Many different dietary supplements are currently marketed for the management of hypertension, but the evidence for effectiveness is mixed. The aim of this systematic review was to evaluate the evidence for or against the effectiveness of green tea (Camellia sinensis) on blood pressure and lipid parameters. METHODS AND RESULTS Electronic searches were conducted in Medline, Embase, Amed, Cinahl and the Cochrane Library to identify relevant human randomized clinical trials (RCTs). Hand searches of bibliographies were also conducted. The reporting quality of included studies was assessed using a checklist adapted from the CONSORT Statement. Two reviewers independently determined eligibility, assessed the reporting quality of the included studies, and extracted the data. As many as 474 citations were identified and 20 RCTs comprising 1536 participants were included. There were variations in the designs of the RCTs. A meta-analysis revealed a significant reduction in systolic blood pressure favouring green tea (MD: -1.94 mmHg; 95% CI: -2.95 to -0.93; I(2) = 8%; p = 0.0002). Similar results were also observed for total cholesterol (MD: -0.13 mmol/l; 95% CI: -0.2 to -0.07; I(2) = 8%; p < 0.0001) and LDL cholesterol (MD: -0.19 mmol/l; 95% CI: -0.3 to -0.09; I(2) = 70%; p = 0.0004). Adverse events included rash, elevated blood pressure, and abdominal discomfort. CONCLUSION Green tea intake results in significant reductions in systolic blood pressure, total cholesterol, and LDL cholesterol. The effect size on systolic blood pressure is small, but the effects on total and LDL cholesterol appear moderate. Longer-term independent clinical trials evaluating the effects of green tea are warranted.

The use of green coffee extract as a weight loss supplement: a systematic review and meta-analysis of randomised clinical trials.

The purpose of this paper is to assess the efficacy of green coffee extract (GCE) as a weight loss supplement, using data from human clinical trials. Electronic and nonelectronic searches were conducted to identify relevant articles, with no restrictions in time or language. Two independent reviewers extracted the data and assessed the methodological quality of included studies. Five eligible trials were identified, and three of these were included. All studies were associated with a high risk of bias. The meta-analytic result reveals a significant difference in body weight in GCE compared with placebo (mean difference: −2.47 kg; 95%CI: −4.23, −0.72). The magnitude of the effect is moderate, and there is significant heterogeneity amongst the studies. It is concluded that the results from these trials are promising, but the studies are all of poor methodological quality. More rigorous trials are needed to assess the usefulness of GCE as a weight loss tool.

Efficacy of calcium supplementation for management of overweight and obesity: systematic review of randomized clinical trials

Numerous dietary supplements are marketed as slimming aids, but the efficacy of most has not been proven. One such slimming aid is calcium. Presented here are the results of a systematic review that aimed to evaluate the evidence for or against the efficacy of calcium supplements for body-weight reduction in overweight and obese individuals. Electronic searches were conducted to identify relevant randomized clinical trials of at least 6 months duration. No restrictions of age, gender, language, or time of publication were imposed. Two reviewers independently determined the eligibility of studies, assessed the reporting quality of the studies included, and extracted data. Twenty-four eligible trials were identified, and seven were included. Five of the randomized clinical trials included were not of good reporting quality. A meta-analysis revealed a small, significant reduction in body weight for calcium compared with placebo (mean difference, (-) 0.74 kg; 95% confidence interval, (-) 1.00-(-) 0.48). A small, significant reduction in body fat favoring calcium over placebo was also noted (mean difference, (-) 0.93 kg; 95% confidence interval, (-) 1.16-(-) 0.71). In conclusion, the evidence from randomized clinical trials suggests calcium supplementation generates small, statistically significant weight loss in overweight and obese individuals, but the clinical relevance of this finding is uncertain.

The effect of chlorogenic acid on blood pressure: a systematic review and meta-analysis of randomized clinical trials.

Several dietary supplements are currently marketed for management of hypertension, but the evidence for effectiveness is conflicting. Our objective was to critically appraise and evaluate the evidence for the effectiveness of chlorogenic acids (CGAs) on blood pressure, using data from published randomized clinical trials (RCTs). Electronic searches were conducted in Medline, Embase, Amed, Cinahl and The Cochrane Library. We also hand-searched the bibliographies of all retrieved articles. Two reviewers independently determined the eligibility of studies and extracted the data. The reporting quality of all included studies was assessed by the use of a quality assessment checklist adapted from the Consolidated Standard of Reporting Trials Statement. Disagreements were resolved through discussion. Seven eligible studies were identified, and five including 364 participants were included. There were variations in the reporting quality of the included RCTs. Meta-analysis revealed a statistically significant reduction in systolic blood pressure in favour of CGA (mean difference (MD): −4.31 mm Hg; 95% confidence interval (CI): −5.60 to −3.01; I2=65%; P<0.00001). Meta-analysis also showed a significant reduction in diastolic blood pressure favouring CGA (MD: −3.68 mm Hg; 95% CI: −3.91 to −3.45; I2=97%; P<0.00001). All studies reported no adverse events. In conclusion, the evidence from published RCTs suggests that CGA intake causes statistically significant reductions in systolic and diastolic blood pressures. The size of the effect is moderate. Few clinical trials have been conducted; they vary in design and methodology and are confined to Asian populations and funded by CGA manufacturers. Large independent trials evaluating the effects of CGA on blood pressure are warranted.

The Use of Garcinia Extract (Hydroxycitric Acid) as a Weight loss Supplement: A Systematic Review and Meta-Analysis of Randomised Clinical Trials

The aim of this systematic review is to examine the efficacy of Garcinia extract, hydroxycitric acid (HCA) as a weight reduction agent, using data from randomised clinical trials (RCTs). Electronic and nonelectronic searches were conducted to identify relevant articles, with no restrictions in language or time. Two independent reviewers extracted the data and assessed the methodological quality of included studies. Twenty-three eligible trials were identified and twelve were included. Nine trials provided data suitable for statistical pooling. The meta-analysis revealed a small, statistically significant difference in weight loss favouring HCA over placebo (MD: −0.88 kg; 95% CI: −1.75, −0.00). Gastrointestinal adverse events were twice as common in the HCA group compared with placebo in one included study. It is concluded that the RCTs suggest that Garcinia extracts/HCA can cause short-term weight loss. The magnitude of the effect is small, and the clinical relevance is uncertain. Future trials should be more rigorous and better reported.

Zanamivir for influenza in adults and children

Objectives To describe the potential benefits and harms of zanamivir. Design Systematic review of clinical study reports of randomised placebo controlled trials and regulatory information Data sources Clinical study reports, trial registries, electronic databases, regulatory archives, and correspondence with manufacturers. Eligibility criteria for selecting studies Randomised placebo controlled trials in adults and children who had confirmed or suspected exposure to natural influenza. Main outcome measures Time to first alleviation of symptoms, influenza outcomes and complications, admissions to hospital, and adverse events in the intention to treat (ITT) population. Results We included 28 trials in stage 1 (judgment of appropriate study design) and 26 in stage 2 (formal analysis). For treatment of adults, zanamivir reduced the time to first alleviation of symptoms of influenza-like illness by 0.60 days (95% confidence interval 0.39 to 0.81, P<0.001, I2=9%), which equates to an average 14.4 hours’ reduction, or a 10% reduction in mean duration of symptoms from 6.6 days to 6.0 days. Time to first alleviation of symptoms was shorter in all participants when any relief drugs were allowed compared with no use. Zanamivir did not reduce the risk of self reported investigator mediated pneumonia (risk difference 0.17%, −0.73% to 0.70%) or radiologically confirmed pneumonia (−0.06%, −6.56% to 2.11%) in adults. The effect on pneumonia in children was also not significant (0.56%, −1.64% to 1.04%). There was no significant effect on otitis media or sinusitis in both adults and children, with only a small effect noted for bronchitis in adults (1.80%, 0.65% to 2.80%), but not in children. There were no data to assess effects on admissions in adults and children. Zanamivir tended to be well tolerated. In zanamivir prophylaxis studies, symptomatic influenza in individuals was significantly reduced (1.98%, (0.98% to 2.54%); reducing event rates from 3.26% to 1.27%, which means 51 people need to be treated to prevent one influenza case (95% confidence interval, 40 to 103). In contrast, the prophylaxis effect on asymptomatic influenza cases was not significant in individuals (risk difference 0.14%, −1.10% to 1.10%) or in households (1.32%, −2.20% to 3.84%). In households treated prophylactically there was an effect on symptomatic influenza (14.84%, 12.18% to 16.55%), but this was based on only two small studies including 824 participants. Prophylaxis in adults reduced unverified pneumonia (0.32%, 0.09% to 0.41%; NNTB (number needed to treat to benefit) 311, 244 to 1086) but had no effect on pneumonia in children or on bronchitis or sinusitis in adults or children (risk difference 0.32%, 0.09% to 0.41%; NNTB 311, 244 to 1086). Conclusions Based on a full assessment of all trials conducted, zanamivir reduces the time to symptomatic improvement in adults (but not in children) with influenza-like illness by just over half a day, although this effect might be attenuated by symptom relief medication. Zanamivir also reduces the proportion of patients with laboratory confirmed symptomatic influenza. We found no evidence that zanamivir reduces the risk of complications of influenza, particularly pneumonia, or the risk of hospital admission or death. Its harmful effects were minor (except for bronchospasm), perhaps because of low bioavailability.

The effect of wind turbine noise on sleep and quality of life: A systematic review and meta-analysis of observational studies.

Noise generated by wind turbines has been reported to affect sleep and quality of life (QOL), but the relationship is unclear. Our objective was to explore the association between wind turbine noise, sleep disturbance and quality of life, using data from published observational studies. We searched Medline, Embase, Global Health and Google Scholar databases. No language restrictions were imposed. Hand searches of bibliography of retrieved full texts were also conducted. The reporting quality of included studies was assessed using the STROBE guidelines. Two reviewers independently determined the eligibility of studies, assessed the quality of included studies, and extracted the data. We included eight studies with a total of 2433 participants. All studies were cross-sectional, and the overall reporting quality was moderate. Meta-analysis of six studies (n=2364) revealed that the odds of being annoyed is significantly increased by wind turbine noise (OR: 4.08; 95% CI: 2.37 to 7.04; p<0.00001). The odds of sleep disturbance was also significantly increased with greater exposure to wind turbine noise (OR: 2.94; 95% CI: 1.98 to 4.37; p<0.00001). Four studies reported that wind turbine noise significantly interfered with QOL. Further, visual perception of wind turbine generators was associated with greater frequency of reported negative health effects. In conclusion, there is some evidence that exposure to wind turbine noise is associated with increased odds of annoyance and sleep problems. Individual attitudes could influence the type of response to noise from wind turbines. Experimental and observational studies investigating the relationship between wind turbine noise and health are warranted.

Chromium supplementation in overweight and obesity: a systematic review and meta‐analysis of randomized clinical trials

The increased prevalence of obesity has made the use of dietary supplements as weight reducing agents highly popular, but their efficacy has not been proven. One such supplement is chromium. The purpose of this review was to evaluate the evidence for or against the efficacy of chromium supplementation in overweight and obese individuals. Electronic searches were conducted in Medline, Embase, Amed and The Cochrane Library. The bibliographies of located articles were also searched. No age, gender or language restrictions were imposed. The reporting quality of identified randomized clinical trials (RCTs) was assessed using a methodological checklist adapted from the Consolidated Standard of Reporting Trials Statement and Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. Thirty‐nine trials were identified and 20 were included. There were variations in reporting quality of included studies. A meta‐analysis of 11 studies showed a statistically significant difference in weight loss favouring chromium over placebo (mean difference (MD): −0.50 kg; 95% confidence interval (CI): −0.97, −0.03). There was a high statistical heterogeneity. Adverse events included watery stools, vertigo, headaches and urticaria. The evidence from available RCTs shows that chromium supplementation generates statistically significant reductions in body weight. The magnitude of the effect is small, and the clinical relevance is uncertain. Future trials should last at least 16 weeks and greater uniformity in the measuring and assessment tools for body composition is recommended.