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Merec Monthly 46


No. 48 March 2012

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Review prescribing of aliskiren
The idolatry of surrogates and the 10 commandments of the new therapeutics
Wound dressings for diabetic foot ulcers no good quality clinical evidence to guide choice
Accredited guidance on combined hormonal and emergency contraception

Review prescribing of aliskiren

The combination of aliskiren with ACE inhibitors or angiotensin receptor blockers (ARBs) is now contraindicated in patients with diabetes (type I or type II) and other patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2.  In all other patient groups, aliskiren in combination with an ACE inhibitor or an ARB is not recommended. Aliskiren (either as monotherapy or in combination with other medicines) is no longer recommended for any patient with severe renal impairment (eGFR <30 mL/min/1.73 m2) 1.

Action
Prescribers should follow the recommendations given in the NICE guideline on hypertension, which was updated in 2011 and outlines a stepwise approach to drug treatment. MeReC Rapid Review No. 4470 outlines the recommendations in the NICE guideline. In developing the NICE full guideline, the guideline development group concluded that there was insufficient evidence of aliskiren’s effectiveness to determine its suitability for use in resistant hypertension. Aliskiren was not included in the drugs recommended by NICE.

In the year from October 2010 to September 2011, over 80,000 aliskiren items were prescribed in general practice in England at a cost of £2.4 million (see MeReC Rapid Review No. 4827 for more details). Prescribing managers may wish to examine local prescribing patterns for aliskiren and ensure local practice is in line with NICE guidance on hypertension.

Background
Following the early termination of the ALTITUDE study, a review of all available safety information on aliskiren was completed in February 2012 by the EMA’s Committee for Medicinal Products for Human Use (CHMP) . The data suggest a risk of adverse outcomes (hypotension, syncope, stroke, hyperkalaemia, and changes in renal function including acute renal failure) when aliskiren is combined with ACE inhibitors or ARBs, especially in diabetic patients and those with impaired renal function.

Aliskiren is now contraindicated in combination with ACE inhibitors or ARBs in patients with diabetes mellitus (type I or type II) or renal impairment (eGFR) < 60 ml/min/1.73 m2), and although less evidence is available in other patient groups, these combinations are not generally recommended. In addition, aliskiren is no longer recommended in any patient with severe renal impairment , i.e. an eGFR <30 mL/min/ 1.73 m2, irrespective of whether it is used in combination with an ACE inhibitor or an ARB, another antihypertensive, or as monotherapy. This latter recommendation is based on an analysis of postmarketing surveillance data, which showed an increased risk of renal adverse events and hyperkalaemia with aliskiren in this patient group.

What is the MHRA advice for healthcare professionals?

  • Prescribers should review the treatment of all patients taking aliskiren in combination with an ACE inhibitor or an ARB at a routine appointment.
  • Aliskirin should not be initiated for new patients who have diabetes or an eGFR <60 mL/min/1.73 m2 if they are already are taking an ACE inhibitor or an ARB.  If existing patients of this type are already taking aliskirin with either an ACE inhibitor or an ARB, the aliskirin should be stopped.
  • Aliskiren in combination with ACE inhibitors or ARBs is not recommended in any other patients. The benefits versus risks of continuing aliskiren treatment should be considered carefully.
  • If aliskiren is discontinued then alternative antihypertensive agents should be used as necessary.
  • Use of aliskiren (either as monotherapy or in combination with other medicines) is no longer recommended in patients with severe renal impairment, i.e. eGFR <30mL/min/1.73 m2.
  • In all patients where aliskiren treatment is continued or initiated, eGFR and glucose tolerance should be monitored at appropriate intervals.
  • Report suspected adverse reactions to aliskiren on a Yellow Card (http://yellowcard.mhra.gov.uk).

Further information on managing hypertension can be found on NHS Evidence and in MeReC Rapid Review No. 4470. The e-learning hypertension section on the NPC website is currently being updated to reflect the new NICE guideline. Hypertension is also featured in a NICE Pathway.

Reference

  1. MHRA. Aliskiren (Rasilez▼): risk of cardiovascular and renal adverse reactions — new contraindications and warnings. Drug Safety Update. March 2012

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The idolatry of surrogates and the 10 commandments of the new therapeutics

An article in the BMJ1 notes that surrogate outcomes are often used in clinical trials instead of patient-oriented outcomes such as death, quality of life, or functional capacity. Using blood glucose and other surrogates in type 2 diabetes as examples, the authors argue that over-interpretation of surrogates and ascribing them undue importance can damage patient care. Reviewing this article, Richard Lehman published the lead author’s ‘10 commandments for the new therapeutics’.

Action
Prescribers, prescribing managers and all those involved in the use of medicines should be cautious in accepting claims for medicines’ effectiveness based on surrogate or ‘disease-oriented’ outcomes. This includes the amount of effort put into controlling surrogate markers of disease rather than into therapies proven to improve patient-oriented outcomes. They should also consider the following suggested ‘10 commandments’ and reflect on whether they should apply them to their own practice:

  1. ‘Thou shalt treat according to level of risk rather than level of risk factor.’
  2. ‘Thou shalt exercise caution when adding drugs to existing polypharmacy.’
  3. ‘Thou shalt consider benefits of drugs as proven only by hard endpoint studies.’
  4. ‘Thou shalt not bow down to surrogate endpoints, for these are but graven images.’
  5. ‘Thou shalt not worship Treatment Targets, for these are but the creations of Committees.’
  6. ‘Thou shalt apply a pinch of salt to Relative Risk Reductions, regardless of P values, for the population of their provenance may bear little relationship to thy daily clientele.’
  7. ‘Thou shalt honour the Numbers Needed to Treat, for therein rest the clues to patient-relevant information and to treatment costs.’
  8. ‘Thou shalt not see detailmen [representatives], nor covet an Educational Symposium in a luxury setting.’
  9. ‘Thou shalt share decisions on treatment options with the patient in the light of estimates of the individual’s likely risks and benefits.’
  10. ‘Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments.’

The BMJ article on the idolatry of the surrogate outcome is reviewed in MeReC Rapid Review No. 4816. Further information on many of the concepts included in the ‘10 commandments’ can be found in the evidence-informed decision-making e-learning section of the NPC website.

Reference

  1. Yudkin JS, et al. The idolatry of the surrogate. BMJ 2011;343:d7995

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Wound dressings for diabetic foot ulcers — no good quality clinical evidence to guide choice

Cochrane reviews of foam dressings1 and hydrogel dressings2 for healing of diabetic foot ulcers have found insufficient good quality clinical evidence to suggest that either of these types of dressings is more effective than other types of dressings.

Action
Healthcare professionals should follow NICE clinical guideline 119 for the management of diabetic foot ulcers. When choosing wound dressings, healthcare professionals from the multidisciplinary foot care team should take into account their clinical assessment of the wound, patient preference and the clinical circumstances, and should use wound dressings with the lowest acquisition cost.

What did the reviews find?
The systematic review of foam dressings1 (six studies, n=157) found that there was no evidence to suggest that foam wound dressings were more effective in healing diabetic foot ulcers than other types of dressings. The systematic review of hydrogel dressings2 (5 studies, n=446) found that there was some evidence that hydrogel dressings were more effective in healing (lower grade) diabetic foot ulcers than basic wound contact dressings. However, this finding was uncertain due to an unclear risk of bias and differences in ulcer severity across the original studies. No randomised controlled trials were identified comparing hydrogel dressings with other advanced dressings. More details of these two reviews can be found in MeReC Rapid Review No. 4804.

These reviews are consistent with other reviews of wound dressings (see MeReC Bulletin Vol 21 No. 1, July 2010) in identifying the lack of good quality RCT evidence to support the use of any particular dressing in diabetic ulcers or other chronic wounds.

Further information can be found on NHS Evidence and in the wound care e-learning materials on the NPC website.

References

  1. Dumville JC et al. Foam dressings for healing diabetic foot ulcers. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD009111. DOI: 10.1002/14651858.CD009111.pub2
  2. Dumville JC, et al. Hydrogel dressings for healing diabetic foot ulcers. Cochrane Database of Systematic Reviews 2011, Issue 9. Art. No.: CD009101. DOI: 10.1002/14651858.CD009101.pub2

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Accredited guidance on combined hormonal and emergency contraception

NHS Evidence accredited provider

The Faculty of Sexual & Reproductive Healthcare (FSRH) has recently published clinical guidance on emergency contraception1 and combined hormonal contraception2. The process used by the Clinical Effectiveness Unit of the FSRH to produce clinical guidance has been accredited by NHS Evidence.

Action
Healthcare professionals providing contraception or contraceptive advice should familiarise themselves with this clinical guidance. A summary of key recommendations is given at the start of each guidance document.

What are the main changes to previous guidance?
For combined hormonal contraception, the main changes from the previous guidance are the inclusion of:

  • All combined hormonal methods (oral contraceptive pills, transdermal patch and vaginal ring)
  • New advice in relation to combined hormonal contraception and antibiotics that do not induce enzymes (see MeReC Rapid Review No. 2586)
  • New missed-pill advice (see also the MHRA Public Assessment Report on combined oral contraceptives, which discusses the rationale for changes to the product information for all combined oral contraceptive pills on when to start taking the pill and actions to take if a pill has been missed)
  • Advice in relation to incorrect use of the contraceptive patch and ring
  • Updated UK Medical Eligibility Criteria for Contraceptive Use.

The most significant change from previous guidance on emergency contraception is the inclusion of ulipristal acetate.

This guidance was signposted in MeReC Rapid Review No. 4786. Further information on contraception can be found on NHS Evidence and in the contraception e-learning section of the NPC website. For more information on the NHS Evidence Accreditation Scheme see the frequently asked questions on the NHS Evidence website.

References

  1. FRSH. Clinical Effectiveness Unit clinical guidance.  Emergency contraception.  August 2011 (updated January 2012)
  2. FRSH. Clinical Effectiveness Unit clinical guidance. Combined hormonal contraception. October 2011

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The National Prescribing Centre (NPC) is responsible for helping the NHS to optimise its use of medicines. NPC is part of the National Institute for Health and Clinical Excellence (NICE), an independent organisation providing national guidance on promoting good health and preventing and treating ill health.
 
© National Institute for Health and Clinical Excellence, 2012. All rights reserved. This material may be freely reproduced for educational and not-for-profit purposes. No reproduction by or for commercial organisations, or for commercial purposes, is allowed without the express written permission of NICE.
Email: copyright@npc.nhs.uk Copyright 2012

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