The New England Journal of Medicine has published the results of a study that aimed to assess the efficacy of irbesartan in reducing outcomes in patients with heart failure with preserved left ventricular ejection fraction.
The study recruited 4,128 participants aged 60 years and above with diagnosis of heart failure (NYHA II, III or IV) and with an ejection fraction of at least 45%. Participants were randomly assigned to treatment with irbesartan 300mg daily or placebo. The primary outcome for the study was a composite of death from any cause or hospital admission for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke).
Over the study period of just over 4 years the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. This difference was not statistically significant. Similarly, there was no difference between the overall death rates and rates of hospital admission when analysed separately.
It is notable that over the period of the study the usage of angiotensin converting enzyme inhibitors (ACEI), beta-blockers and spironolactone increased in both groups. However, mean blood pressure was reduced by an additional 3.6/1.9mmHg in the active arm of the study.
These study results are consistent with the existing evidence and may reflect a poor scientific understanding of this condition. The authors of this study conclude that, "Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction".
Action: Clinicians should continue to implement existing recommendations for heart failure. ACEI should be used in preference to angiotensin receptor blockers with the latter being reserved for patients who are intolerant to ACEIs.
The Medicines and Healthcare products Regulatory Agency (MHRA) has published Drug Safety Update for December 2008 (PDF).
This issue contains a summary of the achievements of the Yellow Card scheme in 2008, a seasonal quiz of drug safety knowledge and stop press summaries for the following areas:
- Conventional (typical) antipsychotics: increased mortality in dementia
- Prograf and Advagraf (tacrolimus): serious medication errors
- Norfloxacin: restricted use in urinary infections
- Hedrin: keep treated hair away from sources of fire
- Melanotan: an unlicensed medicine, the risks of which are unknown
- Tigecycline reformulation affects compatibility: correction
Action: Clinicians will find this publication to be a useful review of current issues in drug safety.
Clinical Knowledge Summaries (CKS) has been updated in December for the following clinical areas:
Action: Clinicians who see patients with any of these conditions may find the updated information useful when reviewing current clinical practice.
The manufacturer of Tacrolimus (Prograf® and Advagraf®) has written to healthcare professionals to highlight the potential for medication errors with these two products.
Prograf is an immediate release formulation of tacrolimus that must be taken twice daily. Advagraf is a prolonged release formulation of tacrolimus that must be taken once daily.
These products are not interchangeable without careful supervision and monitoring. Changes have been agreed with regulatory agencies that will improve the product packaging and leaflets to highlight the differences.
Medication errors have caused serious adverse reactions including acute rejection of transplanted organs and toxicity due to elevated therapeutic levels.
Action: Clinicians should be aware of the potential for medication errors and take particular care when prescribing or dispensing this medication.
PLoS Medicine has published a research article that has assessed the publication rate of efficacy trials submitted to the Food and Drug Administration (FDA) in approved New Drug Applications (NDAs).
The research examined efficacy trial data contained in NDAs submitted in 2001 and 2002 and tried to identify corresponding published clinical trials. 164 efficacy trials were identified with subsequent publication identified for 78% (n = 124). Statistical analysis found that trials with favourable primary outcomes or active comparators were more likely to be published.
The study also found that the statistical significance of the study changed between submission to the FDA and final publication with four of these changes being in favour of the study drug (p=0.38). Nine conclusions changed between the FDA submission and final publication with all the changes favouring the study drug (p=0.0039).
It is also interesting to note that more than 20% of efficacy trials submitted to the FDA remain unpublished 5 years after approval. The authors conclude that, "the information that is readily available in the scientific literature to health care professionals is incomplete and potentially biased".
Action: Clinicians should be aware of the potential for publication bias. Cautious use of drugs with limited data would seem prudent until more data are available to support efficacy claims.