The Medicines and Healthcare products Regulatory Agency (MHRA) has published Drug Safety Update for November 2010 (PDF).
This issue contains drug safety advice warning clinicians of drug interactions that may affect the clinical efficacy of tamoxifen and advising that inadvertent overdose have been reported with the new memantine (Ebixa®) pump device for Alzheimer’s disease.
Additionally, the hot topic section reviews that available data for bisphosphonate use and oesophageal cancer and concludes that there is insufficient evidence of a link.
Finally, in the hot topic section there is a review of some recent safety data for tiotropium (Spiriva®) in the Respimat® device. A recent study using this device found a non-significant increase in all-cause mortality compared with placebo. This finding is at odds with data for the dry powder device (HandiHaler®) where use was associated with a decrease in all-cause mortality. These new results may be a chance finding and further research is required. In the meantime it is recommended that suspected adverse events for either presentation should be reported, the recommended maximum dose should not be exceeded and that the Respimat device should be used with caution in patients with known cardiac rhythm disorders.
Action: Clinicians will find this publication to be a useful review of current issues in drug safety.
The Lancet has published two studies this week that have the potential to reopen the debate about standard versus intensive lipid lowering. The first of these studies is a meta-analysis of statin trials and the second is a randomised controlled trial of simvastatin 80mg versus simvastatin 20mg. Both studies have been reported in the general media (BBC, Telegraph).
The meta-analysis included 26 trials involving 169,138 participants. All of these studies recruited at least 1,000 participants and ran for at least 2 years. 5 of the studies compared a standard statin dose with an intensive dose with the remaining 21 studies comparing statin therapy with a placebo control. This study also compared rates of some adverse events between the study groups. The analysis of the 5 studies with active comparators identified a 15% relative risk reduction (95% CI 11%-18%, p<0.0001) in cardiovascular events. The comparison of adverse effects focussed on haemorrhagic strokes and cancers and found no difference in event rates between the groups.
The authors conclude that, "further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke". They also indicate that for each 1mmol/L reduction in LDL there is a reduction in cardiovascular risk of approximately 20%.
This study does have some limitations. While it did assess adverse events there was no assessment of mild reactions or of liver dysfunction, myopathy and rhabdomyolysis. The conclusions are also based on clinical data alone without any consideration of the relative benefit in terms of additional acquisition costs that would be involved in using more intensive statin therapies.
The second study is the results of the SEARCH study, a randomised controlled trial involving 12,064 participants aged 18 to 80 years with a history of myocardial infarction. Participants were randomly assigned to treatment with either simvastatin 20mg daily or simvastatin 80mg daily. The study ran for a mean of 6.7 years with a composite primary endpoint of coronary death, myocardial infarction, stroke or arterial revascularisation..
At the end of follow up there was a non-significant reduction in major vascular events of 6% (relative risk ratio 0.94, 95% CI 0.88-1.01, p=0.10). There was no apparent difference in the rates of haemorrhagic stroke, vascular death or non-vascular death. There was a higher rate of myopathy (0.9%) in patients taking simvastatin 80mg compared to those taking simvastatin 20mg (0.03%).
The authors conclude that, "the 6% reduction in major vascular events with a further 0·35 mmol/L reduction in LDL cholesterol in our trial is consistent with previous trials". They also suggest that the higher rate of myopathy could be avoided by using other regimens to intensively lower LDL.
The conclusions of this study are restricted as it did not reach statistical significance in the primary outcomes. The authors also note that over the duration of the study, the introduction of more aggressive targets had the effect of reducing the net difference in LDL cholesterol between the two groups as more non-study treatments were started. The suggestion that alternative intensive lipid regimens could be used to reach lower targets and avoid the risk of myopathy seen with simvastatin 80mg does not consider the relative benefits in terms of higher acquisition costs.
Action: These two studies both appear to champion treating LDL to lower levels to prevent cardiovascular events. Neither study has assessed the impact of milder adverse drug reactions nor has any assessment be made of the relative benefits of more intensive lipid lowering treatments versus the acquisition costs to the NHS.
The Association of the British Pharmaceutical Industry (ABPI) has voted in favour of several changes to the Code of Practice to "increase transparency and trust".
The changes will be incorporated into the Code of Practice on the 1st January 2011 but enforcement of the newly introduced requirement will start of the 1st May 2011. The main changes are:
- the industry will no longer provide branded promotional items to healthcare professionals
- inexpensive items to be passed on and used by patients as part of a formal patient support programme are allowed
- companies will also have to declare payments to healthcare professionals each year
More details of the changes are available from the Prescription Medicine Code of Practice Authority (PMCPA). An updated version of the Code of Practice will be available to download shortly with print copies available by the end of the year.
Action: Clinicians should be aware of the changes to the ABPI Code of Practice and the phased introduction of the new requirements. These most recent updates are the end of the line for drug name branded pens and sticky pads!
Diabetes Care has published the results of a study that aimed to assess the effect of metformin on cancer incidence in a consecutive series of insulin-treated patients.
The study identified 1,340 consecutive type 2 diabetic outpatients (mean age 63, 56% female). Participants had no history of cancer and all were started on insulin therapy between 1998 and 2007 in Florence, Italy. Incident cancer diagnoses were identified using hospital admission data or the Mortality Register (for cancer deaths).
112 patients were identified with incident cancer (29 gastrointestinal, 16 lung, 14 pancreatic, 53 others) over a media follow up of 73.9 months (approximately 6 years). These cases were matched to controls for age, gender and BMI at insulin initiation from a cohort of 370 patients. In those patients who were prescribed metformin that was a significantly reduced risk of cancer (odds ratio 0.46, 95% CI 0.25-0.85, p=0.014).
The authors conclude that, "the reduction of cancer risk could be a further, relevant reason for maintaining metformin in insulin-treated patients ".
The authors note that there are limitations in the data and therefore the analysis. Prescription bias could not be ruled out and some patients may have been misdiagnosed as diabetic. Also, the greater incidence of cancer in those patients that did not receive metformin may be due to co-morbidities.
Action: Clinicians should be aware of this small study. The results of this study may be useful when discussing the risks and benefits of metformin treatment.
Clinical Knowledge Summaries (CKS) has been updated in November 2010 for the following clinical areas:
Action: Clinicians who see patients with any of these conditions may find the new and updated information useful when reviewing current clinical practice.