No evidence for combination or alternating paracetamol and ibuprofen in febrile children

The PITCH study is a UK randomised controlled trial of paracetamol, ibuprofen, and a combination of the two drugs in 156 febrile children (axillary temperatures of at least 37.8°C and up to 41.0°C), aged 6 months to 6 years in primary care. Parents were given standardised verbal and written advice on the appropriate use of loose clothing and encouraging children to take cool fluids. They were also given advice on how to administer the analgesia for up to 48 hours: paracetamol every 4-6 hours (maximum of four doses in 24 hours) and ibuprofen every 6-8 hours (maximum of three doses in 24 hours). The dose was determined by the child’s weight: paracetamol 15 mg/kg per dose and ibuprofen 10 mg/kg per dose.

All parents received two medicine bottles; either both active or one containing the active drug and the other placebo. Given the differences in dosing, the parents were aware of which was paracetamol/placebo and which was ibuprofen/placebo.

The two primary outcomes were the time without fever (<37.2°C) in the first four hours after administration the first dose and the proportion of children reported as being normal on the discomfort scale at 48 hours.

The researchers reported the following results based on an intention to treat analysis:

• Paracetamol plus ibuprofen was superior to paracetamol in terms of less time with fever in the first four hours (adjusted difference 55 minutes, 95% CI 33 to 77; P<0.001) but not superior to ibuprofen alone (16 minutes, –7 to 39; P=0.2).
• For less time with fever over 24 hours, paracetamol plus ibuprofen was superior to paracetamol (4.4 hours, 2.4 to 6.3; P<0.001) and to ibuprofen (2.5 hours, 0.6 to 4.4; P=0.008).
• Combined therapy cleared fever 23 minutes (2 to 45; P=0.025) faster than paracetamol alone but no faster than ibuprofen alone (–3 minutes, 18 to –24; P=0.8).
• No benefit was found for discomfort or other symptoms, although power was low for these outcomes. Adverse effects did not differ between groups.

The authors concluded that, “parents, nurses, pharmacists, and doctors wanting to use medicines to supplement physical measures to maximise the time that children spend without fever should use ibuprofen first and consider the relative benefits and risks of using paracetamol plus ibuprofen over 24 hours”.

An accompanying editorial notes that there is no persuasive evidence for recommending a combination or an alternating regimen of paracetamol and ibuprofen. Other suggestions made include improving the precision of diagnosis in febrile children, the importance of fluid intake and sensible clothing and weighing the child to determine the most appropriate dose of antipyretic. The editorialist concludes that ibuprofen is the most suitable antipyretic to use because of its longer duration of action. 

Br Med J 2008; 337: a1302 (link to abstract); Br Med J 2008; 337: a1409 (Editorial; link to extract)

 

Computerised cognitive-behavioural therapy for depression: systematic review

Background

Computerised cognitive–behavioural therapy (CCBT) is used for treating depression and provides a potentially useful alternative to therapist cognitive–behavioural therapy (CBT).

Aims

To systematically review the evidence for the effectiveness of CCBT for the treatment of mild to moderate depression.

Method

Electronic databases were searched to identify randomised controlled trials. Selected studies were quality assessed and data extracted by two reviewers.

Results

Four studies of three computer software packages met the inclusion criteria. Comparators were treatment as usual, using a depression education website and an attention placebo.

Conclusions

There is some evidence to support the effectiveness of CCBT for the treatment of depression. However, all studies were associated with considerable drop-out rates and little evidence was presented regarding participants’ preferences and the acceptability of the therapy. More research is needed to determine the place of CCBT in the potential range of treatment options offered to individuals with depression.

The British Journal of Psychiatry (2008) 193: 181-184. doi: 10.1192/bjp.bp.106.025981

Br J Psychiatry 2008; 193: 181-4

Eva Kaltenthaler, BSC, MSc, PhD, Glenys Parry, BA, PhD, DipClinPsych, CPsychol, FBPsS and Catherine Beverley, MSc, BSc, MCLIP

School of Health and Related Research (ScHARR), University of Sheffield

Michael Ferriter, BA, MPhil, MSc, PhD

Department of Research and Development Nottinghamshire Healthcare NHS Trust, Rampton Hospital, Nottingham, UK

 

 

Aggregated trial data does not indicate increased cancer risk with ezetimibe

Analysis of data from three trials involving ezetimibe does not support an association with increased risk of cancer.

Results from the SEAS trial of simvastatin plus ezetimibe suggested the possibility of an increased risk of cancer associated with ezetimibe use. Analyses of data from previous lipid lowering trials involving over 90,000 participants found no association between lipid lowering with a statin alone, and the results from SEAS include data from only a few people (101 people and 65 cancers). This paper reports further analysis with a larger dataset including cancer data from two further ongoing trials that include ezetimibe. Agreement to unblind cancer data only was obtained from independent data monitoring committees for the SHARP and IMPROVE-IT studies: these were compared with the data from SEAS. Analysis was restricted to patient with cancers recorded as having onset after starting treatment.

SHARP includes 9,264 patients, and at the point of analysis had a mean follow-up of 2.7 years; IMPROVE-IT currently includes 11,353 patients with a mean follow-up of 1.0 year. When data from the two studies were combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P=0.61) and no significant excess at any particular site.

In patients receiving ezetimibe, there was a numerical excess of deaths due to cancer, but the numbers were small and the difference not statistically significant (97, vs. 72 in the control group; P=0.07), however there were fewer other cancers in the ezetimibe group compared to control – also not statistically significant (216, vs. 254 in the control group; P=0.08).

On this analysis, the authors conclude that the data do not provide any credible evidence that ezetimibe has any adverse effects on the rates of cancer. As a result, the two trials will continue until their planned finish dates, with regular interim analysis of safety data.

New Engl J Med, published early online 2 September 2008; doi: 10.1056/NEJMsa0806603 (link to abstract)

 

Prophylaxis Sometimes Needed - Childhood migraine

Prophylaxis Sometimes Needed

Prophylactic treatment may be indicated for children who have migraine attacks that are prolonged, frequent (>2 severe attacks per month) or incapacitating and are not relieved by symptomatic treatment.^[3,4] Prophylaxis may also be considered if attacks predictably occur at critical times, such as during examinations. However, nondrug treatments can be highly effective and should be tried before drug therapy is initiated, and continued in a complementary role. If prophylactic drug treatment is required, it should be prescribed and individually tailored by a specialist.^[4]

When initiating prophylactic treatment, a trial of the drug for 6 to 12 weeks is warranted. If effective, the drug should be continued for 6 months and then the patient reassessed.^[4] If the first drug is not effective, a second and then a third, if necessary, can be tried.^[3]

A number of the options for migraine prophylaxis in adults, as previously reviewed [see article entitled 'A lot of ammunition but does migraine prophylaxis hit the target?' Drugs & Therapy Perspectives 1999 June 7; 13 (11): 5-8], have been investigated in children and adolescents. However, only a few drugs have proven to be effective. In the absence of a consistently effective or any one clearly superior drug, the choice of drug may be guided by the characteristics of the child and child/parent preference after discussing the adverse effect profiles of the various available agents (see table 2).^[3,4]

A Few Possible Options

The strongest evidence for efficacy is for flunarizine (see table 2). Flunarizine 5 or 10 mg/day reduces the frequency and duration of migraine in children.^[11,12] It appears to be at least as effective as comparator agents, including propranolol, aspirin and nimodipine.^[13,14,21] However, the use of flunarizine may be limited by adverse effects including bodyweight gain and drowsiness.

Propranolol appeared promising as a prophylactic agent for migraine in children at first,^[18] but later data have been less positive^[19,20] (see table 2). Despite its established efficacy in adults,^[10] propranolol can not presently be recommended as the first choice for migraine prophylaxis in children, although it may be worth trying.^[3] However, it should be remembered that the use of propranolol is contraindicated in children with asthma.

Results from double-blind, placebo-controlled trials of pizotifen have been inconsistent (see table 2).^[15,17] However, the drug does appear to have some efficacy when data from uncontrolled trials and comparative trials with lisuride and tryptophan are taken into account.^[3]

Results Equivocal for Many Drugs

At least some efficacy has been shown for a number of other drugs, including amitriptyline, papaverine, nimodipine, cyproheptadine and trazodone, but more data are needed to clarify if they will be useful prophylactic agents for migraine in children. The prophylactic effects of clonidine appear to be limited and are only seen in patients with migraine with aura.^[3,4]

Beta-Blockers and calcium antagonists other than those already discussed, NSAIDs, dihydroergotamine mesylate, tryptophan and carbamazepine have failed to show any real efficacy in this indication.^[3,4]

Valproic acid (sodium valproate) has not been tested in controlled studies in children.^[4]

Some Individuals May Benefit

Despite the less than encouraging results from many of the trials of prophylactic drugs, it is possible that some individual patients will improve dramatically with a specific drug.^[3] This may reflect the heterogenous nature of migraine.

 

Meta-analysis: antibiotics for acute sinusitis

Antibiotic treatment has a small therapeutic benefit over placebo in acute sinusitis with an increased risk of adverse effects, according to a meta-analysis.

The authors note that acute sinusitis is one of the more frequent reasons for prescription of an antibiotic in primary care, but that there is still controversy over whether they are effective. This review aimed to assess how safe and effective antibiotics were for acute sinusitis. The authors carried out a literature search primarily using Medline via PubMed, supplemented with Scopus. Eligible studies were randomised, double-blind placebo-controlled trials of any antibiotic for acute sinusitis. For each included study, data on its design and outcomes were extracted for meta-analysis; the primary outcome was cure or improvement in clinically assessable patients, between 7 and 15 days from the start of treatment.

Initial searches yielded 194 potentially relevant articles, of which 29 were selected on the basis of title and abstract; 16 of these, plus one further study identified through an updated search, fitted the eligibility criteria and were included in the meta-analysis. All 17 were high quality (Jadad score 4 or 5), and most were carried out in Europe or the US. Total number of participants was 3,291, including 376 children. The antibiotic most often used was amoxicillin (10 studies) followed by phenoxymethylpenicillin (4 studies) and co-amoxiclav (3 studies). Five studies had more than one antibiotic treatment group.

There were 16 studies (n=2,648) reporting the primary outcome of cure or improvement, and in these, more patients were cured or improved in the antibiotic group (OR 1.64; 95% CI, 1.35 to 2.00).

Twelve studies (n=1,813) specifically reported cure rates, and in these more patients were cured in the antibiotic groups compared to placebo (odds ratio 1.82; 95% CI, 1.34 to 2.46).

Twelve studies (n=1,963) reported adverse effects: in these, patients in the antibiotic group were more likely to report adverse effects (OR 1.87; 95% CI, 1.21 to 2.90). Study withdrawals because of adverse events did not differ between compared treatments, and neither did disease complications, or disease recurrence.

The authors conclude that antibiotic treatment has a small therapeutic benefit in acute sinusitis, but that this is matched with a corresponding increase in adverse events. There was no indication in the meta-analysis of any effect on disease complications or recurrence. Accordingly, they suggest that antibiotics should not be used routinely for these patients but should be reserved for those with a high probability of bacterial disease. To support this, research is needed to improve identification of this group.

Lancet Infect Dis 2008; 8: 543-52 (link to abstract)

 

Ivabradine for patients with stable CAD and left-ventricular systolic dysfunction

According to findings from a Phase III trial published early online in the Lancet, ivabradine does not improve cardiac outcomes in patients with stable coronary artery disease (CAD) and left-ventricular systolic dysfunction (LVD).

The authors note that high heart rate has been shown to be an independent predictor of mortality in CAD patients; lowering heart rate could therefore reduce mortality and cardiovascular events, but this has not been tested as current agents (e.g. beta-blockers) have other cardiovascular actions that would confound the results.  Ivabradine is a selective sinus node inhibitor which decreases resting heart rate – it has no effect on blood pressure, myocardial contractility, intracardiac conduction, or ventricular repolarisation.  They therefore designed this trial (BEAUTIFUL - morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction) to see whether the addition of ivabradine to standard treatment to lower heart rate could reduce cardiac death and mortality in patients with CAD and LVD.

A total of 10,917 adults (over 55 years or over 18 years if diabetic) with CAD and a left ventricular ejection fraction of <40% were randomised to double-blind treatment with ivabradine (n=5,479; 5mg initially, increasing up to 7.5mg twice daily) or placebo (n=5,438).  For inclusion, patients had to be in sinus rhythm, have a resting heart rate of at least 60bpm, and have been stable in terms of angina and/or heart failure symptoms for the previous three months (and on stable doses of conventional cardiovascular medicine for the previous one month – this was continued during the study).  Treatment was reduced/ discontinued if the heart rate fell below 50bpm and/or in the presence of symptoms of bradycardia.  The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure (intention-to-treat analysis).

The mean age of the group was 65 years, and 83% were male.  The mean heart rate at baseline was 71.6 bpm, and the mean LVEF was 32.4%. A total of 94% patients were receiving aspirin or an anticoagulant, 87% a beta-blocker; 74% statins, and 90% an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (no statistically significant differences between the two groups). 

After a median follow-up of 19 months, the main findings were as follows:

• The mean difference between the treatment groups (placebo minus ivabradine) in change from baseline resting heart rates was 7.2 bpm (95% CI 6.8–7.5) at 6 months, 6.4 bpm (6.0–6.8) at 12 months, 6.0 bpm (5.6–6.5) at 18 months, and 5.6 bpm (5.1–6.2) at 24 months
• The primary endpoint occurred in 844 patients (15.4%) in the ivabradine group and 832 (15.3%) in the placebo group (hazard ratio [HR] 1.00, 95% CI 0.91–1.1, p=0.94)
• In a pre-specified subgroup of patients with a heart rate of ≥70bpm, there was no effect of ivabradine on the primary endpoint (hazard ratio 0.91, 95% CI 0.81–1.04, p=0.17) but it was found to reduce the incidence of the following secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49–0.84, p=0.001) and coronary revascularisation (0.70, 95% CI 0.52–0.93, p=0.016).

The authors suggest that ivabradine could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater.  This trial was however not powered to test for statistically significant differences in this subgroup for the secondary endpoints; these findings would need confirmation in a prospective study.

Lancet, published early online 31 August 2008; DOI:10.1016/S0140-6736(08)61170-8 (main study, link to abstract); Lancet, published early online 31 August 2008;

 

MHRA drug safety advice: Risk of serious and fatal overdose with fentanyl patches

The September 2008 edition of ‘Drug Safety Update’ from the MHRA contains advice on the risk of overdose with fentanyl patches, following spontaneous reports from healthcare professionals, patients, and carers, of unintentional overdose due to dosing errors, accidental exposure, and exposure of the patch to a heat source.  

Factors identified as possibly related to unintentional overdose include dosing errors (by healthcare professionals, patients, or caregivers); accidental exposure (particularly in children); and exposure of the patch to a heat source, possibly resulting in increased fentanyl absorption. These reports also provide some evidence of inappropriate prescribing of fentanyl patches, including prescribing in unlicensed indications and in opioid-naïve patients.

The MHRA has issued the following advice for healthcare professionals (taken directly from the article):

• Healthcare professionals, particularly those who prescribe and dispense fentanyl patches, must fully inform patients and caregivers about directions for safe use:
• follow the prescribed dose
• follow the correct frequency of patch application
• ensure that old patches are removed before applying a new one
• patches must not be cut
• avoid touching the adhesive side of patches and wash hands after application
• follow instructions for safe storage and disposal of used or un-needed patches
• Increased body temperature, exposure of patches to external heat sources, and concomitant use of CYP3A4 inhibitors may lead to potentially dangerous rises in serum fentanyl levels. Concomitant use of other CNS depressants might also potentiate adverse effects from fentanyl

Healthcare professionals, particularly those who prescribe and dispense fentanyl patches, should ensure that patients and caregivers are aware of the signs and symptoms of fentanyl overdose. Patients and caregivers should be advised to seek medical attention immediately if overdose is suspected Patients who experience serious adverse events should have the patches removed immediately and should be monitored for up to 24 hours after patch removal.

Drug Safety Update: Volume 2, Issue 2 September 2008 (link to abstract)