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Prescribing Advice for GPs

An NHS Prescribing Advisers' Blog

Publication Bias

Studies that are published are commonly positive about the study drug with very few showing a negative outcome. This is because of Publication Bias.

Publication Bias occurs when only certain information, namely positive trial results, is published in journals.

This is an age old tactic as many scientists, upon getting a poor result, blame the experiment (or study) and set off to conduct the study again until they get the expected answer. However, in a well constructed and properly randomised and blinded study this should not be the case and the result perhaps should be made available.

For example, the results of the Serevent Multicentre Asthma Research Trial (SMART) have not been published despite the fact that the study was started in 1996. Action by the Food and Drugs Administration has brought about labelling changes in the United States following safety concerns raised by the study.

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UK Vioxx patients lose appeal

The BBC report that over 200 patients who took the drug Rofecoxib (Vioxx) have lost an appeal for legal aid meaning that many will not be able to bring their case to court.

In addition, the insurance companies that back "no-win, no-fee" style claims have refused to provide cover. Some of the claimants are now considering trying to make their case in the USA. The decision on whether a UK citizen can bring a claim in the United States will be made by the American Judge.

Action: Clinicians may wish to be aware of the latest information regarding Rofecoxib.

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Manipulate Graphical Data

Data represented in graphs can be manipulated by altering the axes of the graph. There are many ways the data can be altered including:

  • using different scales on graphs that are side by side
  • using log scales to compress the differences
  • using amputated axes to exaggerate the differences
  • origins of graphs not starting at zero

By using these tricks a graphical representation of the data can be altered to make it visually more impressive. The distance between lines on the same graph can be enhanced or reduced.

Look out for enhancements where a demonstration of difference would be expected by the reader, for example in the primary outcome of a study. Look out for reductions where similarities between treatments would be expected by the reader, for example adverse effects.

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Poor Comparators

One of the easiest ways to show that one drug is effective compared to another is to choose a poor comparator. This can be done in several different ways:

  • compare with a low or sub-therapeutic dose to enhance the effects of the study drug
  • compare with a pharmacologically poor molecule to enhance the effects of the study drug
  • compare with a high dose to minimise the side effects of the study drug
  • compare against a drug or dose not used in current clinical practice

When reading a study ask yourself, "Is this a valid comparison, would I have chosen to use this comparator in the study?"

For example, in the ASCOT Study the comparator arm studied doses of atenolol 100mg and bendroflumethiazide 1.25mg in Hypertension. Atenolol 100mg is no more effective than atenolol 50mg and bendroflumethiazide is used at a starting dose of 2.5mg in the UK.

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Evidence lacking for COX-2 GI Safety

A population based nested control analysis1 published in the BMJ has failed to find consistent evidence of enhanced safety against gastrointestinal (GI) events with any of the new cyclo-oxygenase-2 (COX-2) inhibitors compared with non-selective non-steroidal anti-inflammatory drugs (NSAIDs).

This analysis looked at 10,892 cases of upper gastrointestinal events in patients over the age of 25, between August 2000 and July 2004. Each case was matched with up to 10 controls and odds ratios were calculated and adjusted for other NSAIDs, smoking, comorbidity, deprivation, selective serotonin reuptake inhibitors, tricyclic antidepressants, statins, aspirin and ulcer healing drugs.

Overall, there was no strong evidence of a decreased GI risk with the newer COX-2 NSAIDs compared to non-selective NSAIDs. Concurrent use of ulcer-healing drugs reduced the risk of adverse GI events in patients taking COX-2 and non-selective NSAIDs.

Individual analysis of certain NSAIDs demonstrated that ulcer healing drugs in patients taking diclofenac did not alter GI risk, although the authors say this could be due to chance in the data analysed. Also, the interaction between celecoxib and ulcer healing drugs was not significant probably because of the small numbers of patients taking this drug.

The authors of this paper state that as ulcer healing drugs lower the GI risk in patients taking COX-2 NSAIDs that these drugs are not as safe as originally thought. However, all NSAIDs carry a GI risk, the risk with COX-2 selective NSAIDs is lower but not reduced to a baseline level of risk.

Action: This analysis raises again the safety profile of NSAIDs. All NSAIDs carry a GI and cardio-vascular risk, including the newer COX-2 selective NSAIDs. The MHRA advice, as previously covered, applies to all NSAID prescribing:

  • Use paracetamol as first line where ever possible
  • If necessary, use the NSAID with the lowest overall risk (usually Ibuprofen)
  • At the lowest effective dose
  • For the shortest period
  • And only use one NSAID at a time

References:

  1. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005;331:1310-1316

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