NHS Greater Glasgow & Clyde Area Drug and Therapeutics Committee
Greater Glasgow and Clyde Medicines
Medicines Update Primary Care

PostScript Primary Care (Sept '13)

Dual Antiplatelet Therapy

From April 2013, patients presenting with Troponin positive Acute Coronary Syndromes (ACS) have been treated with dual anti-platelet therapy (DAPT) consisting of aspirin plus ticagrelor. This follows the PLATO (PLATelet Inhibition and Patient Outcomes) study which included 18,624 patients presenting within 24 hours of onset of ACS symptoms who were initially managed medically, or with percutaneous coronary intervention (PCI), or with coronary artery bypass grafting. Ticagrelor 90mg twice daily showed superiority to clopidogrel 75mg daily in reducing the composite endpoint of cardiovascular death, myocardial infarction or stroke. The NHSGGC Guideline for Antiplatelet Therapy in Secondary Prevention of Coronary Heart Disease recommends how long patients should receive ticagrelor 90mg twice daily in addition to aspirin:

Management Weeks of Ticagrelor
Medical (Troponin +ve ACS) 12
Balloon Angioplasty Alone 12
PCI with Bare Metal Stent 12
PCI with Drug Eluting Stent 26

 

For patients undergoing elective PCI, DAPT consists of aspirin and clopidogrel 75mg daily: patients treated with a bare metal stent (or balloon angioplasty alone) should receive DAPT for four weeks and patients treated with a drug eluting stent should receive DAPT for 26 weeks. Patients with a history of transient ischaemic attack or ischaemic stroke should revert to indefinite monotherapy with clopidogrel 75mg daily thereafter.


A significant number of ACS patients are still being treated with aspirin plus clopidogrel, this is largely due to concerns around bleeding, adverse drug reactions (ADRs) and drug interactions.  ADRs with ticagrelor are similar to clopidogrel, with the exception of dyspnoea which PLATO reported in 14% of patients (versus 8% with clopidogrel). If persistent and troublesome, consider switching to clopidogrel for the remainder of the treatment course. 
Secondary Care provides 28 days of DAPT on discharge. The accompanying patient and GP information leaflets state how long the patient should receive the remainder of their treatment in primary care. The only exception are patients on a compliance aid for whom Secondary Care supply seven days treatment. Further information is available in the NHSGGC Shared Care Protocol for Ticagrelor.

DAPT should not be continued beyond the intended duration. When added to prescription, the stop date should be annotated on the dose instructions; for example ‘Ticagrelor tablets 90mg – one to be taken morning and night until 31.12.2013’. Including this information in the dose instructions affords an additional safety net, as the stop date is available to the patient and/or carer. Practices should ensure that repeat prescriptions are inactivated following the end of the specified duration.

Primary Care Respiratory Prescribing Tools

Considerable work has been done across Greater Glasgow & Clyde practices in the last two years with regard to prescribing indicators for high-dose inhaled corticosteroids (ICS) in asthma and chronic obstructive pulmonary disease (COPD), leukotriene receptor antagonist and mucolytic prescribing. Three new prescribing tools have been developed to support prescribing in asthma and COPD.  The tools promote cost effective prescribing of inhaler devices in asthma and COPD without compromising patient care and offer guidance on the step-down of high-dose combination inhalers (ICS plus long-acting beta2 agonist (LABA)) in stable asthmatic adults.

Primary Care Adult Asthma (18 years and over) inhaler device guide and COPD inhaler device guide
The two inhaler device guides recommend the most cost-effective inhaler device at each stage of asthma and COPD management.  A metered dose inhaler and dry powder inhaler device are given as treatment options at each stage.  The decision about device suitability will vary with each individual patient. The inhaler device guides are available from the NHSGGC prescribing website.

A guide to stepping down stable asthmatic ADULT patients (18 years and over)  from high dose ICS/LABA combination inhalers
Asthma guidelines recommend a stepwise approach to symptom management; stepping up therapy to achieve control of symptoms and stepping down therapy to a lower dose when control is good. Asthma patients should be regularly reviewed and titrated to the lowest dose of ICS that controls symptoms*. The BTS/SIGN British Guideline on the Management of Asthma supports NHSGGC audit findings that ‘stepping down therapy once asthma is controlled is recommended, but often not implemented, leaving some patients over-treated.’  Step down should be considered if the patient has been stable for at least 12 weeks.

The new step-down guide offers the prescriber practical advice on how to step down stable adult asthmatics on high-dose combination inhalers to lower strength combination inhalers in line with BTS/SIGN guidelines.  The step-down guide is available from your local prescribing support pharmacist.

Inhaler Device Patient Information Leaflets (PILs)
A set of NHSGGC inhaler device PILs has been produced giving patients and staff, step by step instructions for using individual inhaler devices.  Written patient information is useful to support verbal and practical advice about how to use inhaler(s). PILs are available for Accuhaler, Easi-Breathe, Easyhaler, Handihaler, Metered-Dose Inhaler, Turbohaler, Volumatic and Aerochamber Spacers.  Printable versions of all PIL’s are available from the NHSGGC prescribing website.

*Complete asthma control is defined in SIGN/BTS guideline as: no daytime symptoms, no night-time awakening due to asthma, no need for rescue medication, no exacerbations, no limitations on activity including exercise, normal lung function (in practical terms FEV1 and/or PEF>80% predicted or best), minimal side effects from medication.

Reducing Temazepam Prescribing

Temazepam costs have risen nine-fold since September 2012, see figure below.  From NHSGGC benzodiazepine general practice audits, we are aware that the majority of temazepam prescribing is for long-term use: more than 4 weeks.  

Items= prescription numbers
PD Paid GIC excl.BB = Paid gross ingredient cost excluding Broken Bulk cost

Current advice recommends hypnotics should only be used for short-term (2-4 weeks) relief of insomnia when it is severe, disabling or causing extreme distress.¹ All hypnotic drugs should only be used for short periods because of tolerance to the drug and the risk of dependency.²

Efficacy
Hypnotics such as benzodiazepines and z-hypnotics are marginally more effective than placebo, providing an extra 25 minutes of sleep per night (Number Needed to Treat = 13).³  83% (20 of 24) of studies included in this meta-analysis where for short-term treatment, less than 21 days. Other meta-analysis, where the majority of patients receive short courses (<21 days), demonstrate similar marginal benefits.4,5

Harm
Glass et al. also demonstrate that people receiving hypnotics commonly experience adverse effects: cognitive impairment (memory loss, confusion, disorientation); psychomotor impairment (dizziness, loss of balance, or falls); and/or morning hangover effects (Number Needed to Harm = 6).³ It is well known that benzodiazepines cause these adverse effects but they can also cause emotional blunting and aggravate depression;6 however, these adverse effects are also commonly caused by z-hypnotics with zopiclone possibly impairing driving performance more than benzodiazepines. 7,8  Larger hypnotic doses are also known to be associated with a higher risk of falls and some suggest an increased risk of dementia with benzodiazepine use. 9,10

Addressing the hypnotic costs
Reviewing patients is the optimal method to address the hypnotic burden: drug induced costs to patients and financial costs to public services. 

Brief interventions, such as lettering patients or single GP consultations, for people receiving long-term benzodiazepines and z-hypnotics is an effective and efficient strategy to reduce or stop prescribing with one cessation for every 12 letters sent.11  Previous work within NHSGGC general practices using combinations of letters, consultations and managed reductions have achieved more than 30% reductions in benzodiazepine and z-hypnotic prescribing.12,13

Are patients appropriate for review, reduction or stopping?
Some patients may be inappropriate to reduce or stop due to their history eg epilepsy, or palliative care, whereas those under the care of mental health teams may be appropriate for managed reduction if agreed between general practice and the mental health team.  If patients are inappropriate to reduce and stop, consider if they are over ordering their temazepam and should this be limited to a 28 day supply as per Controlled Drug legislation and if weekly or daily dispensing is appropriate. 

Managed withdrawal can be effective, as long as patients are informed:
• Why their hypnotic is being reviewed: lack of long-term efficacy, high risk of side effects and some may have total doses higher than that licensed.
• Why it would be appropriate to reduce with the aim of stopping eg minimise side effects such as cognitive dysfunction, paradoxical anxiety/agitation, falls, emotional blunting
• How the managed reduction will work: as a stepped process with a flexible rate of reduction no quicker than every two weeks
• Reason to change to longer acting diazepam: reduce withdrawal risk, more flexible dosing due to 2mg or 5mg tablets which can be easily halved.
• Size of the dose reduction: one quarter to one tenth of the total prescribed daily dose with smaller 1mg reductions as the dose gets smaller.  See tables below for examples of temazepam reduction.

More information on selecting patients and managing reductions is available in the Ashton Manual and NICE Clinical Knowledge Summaries.

 

Temazepam 10mg at night  
To diazepam equivalent at night†  
Week 1 5mg
Week 3 4mg
Week 5 3mg
Week 7 2mg
Week 9 1mg
Week 11 Stop

 

Temazepam 20mg at night  
To diazepam equivalent at night†  
Week 1  10mg
Week 3  8mg
Week 5  6mg
Week7  4mg
Week 9  3mg
Week 11  2mg
Week 13 1mg
Week 15 Stop

 

†Caution: As diazepam dose is an equivalent, not an exact dose, some people such as the elderly may experience next day sedation due to diazepam’s long half-life.  Therefore, a switch from 10mg temazepam to 4mg diazepam (or 20mg temazepam to 8mg diazepam) may be appropriate with follow up review within 7 days for some patients.

A 10 year follow up study indicates that for patients who stopped benzodiazepines: 59% were benzodiazepine free at 10 years and 14% restarted but were prescribed a lower dose.  Being abstinent at 21 months after the intervention predicted abstinence at 10-year follow-up.14

Useful websites and information
Ashton Manual: http://www.benzo.org.uk/manual/contents.htm
MHRA benzodiazepine learning module: http://www.mhra.gov.uk/ConferencesLearningCentre/LearningCentre/Medicineslearningmodules/Reducingmedicinerisk/Benzodiazepineslearningmodule/index.htm

NICE CKS: http://cks.nice.org.uk/benzodiazepine-and-z-drug-withdrawal#!topicsummary
National Prescribing Centre: http://www.npc.nhs.uk/qipp/qipp_elearning/hypnotics_elearning.php

References
1. Committee on Safety of Medicines. Current Problems: Benzodiazepines, dependence and withdrawal symptoms. 1988; Number 21:1-2.
2. National Institute for Clinical Excellence.  Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia.  Technology Appraisal 77, April 2004. http://www.nice.org.uk/nicemedia/live/11530/32845/32845.pdf
3. Glass J, Lanctot KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005;331(7526):1169.
4. Buscemi N, Vandermeer B, Friesen C, et al.. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs. Journal of General Internal Medicine 2007;22(9):1335-1350.
5. Huedo-Medina TB, Kirsch I, Middlemass J, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ 2012;345:e8343.
6. Ashton H. Adverse effects of prolonged benzodiazepine use. Adverse Drug Reaction Bulletin 1986;118:440-443.
7. Kripke DF. Greater incidence of depression with hypnotic use than with placebo. BMC Psychiatry 2007;7:42.
8. Barbone F, McMahon AD, Davey PG, et al.  Association of road-traffic accidents with benzodiazepine use. Lancet 1998;352(9137):1331-1336.
9. Sterke CS, van Beeck EF, van der Velde N, et al. New insights: dose-response relationship between psychotropic drugs and falls: a study in nursing home residents with dementia. J Clin Pharmacol 2012;52(6):947-955.
10. Billioti de Gage S, Begaud B, Bazin F, Verdoux H, et al. Benzodiazepine use and risk of dementia: prospective population based study. BMJ 2012;345:e6231.
11. Mugunthan K, McGuire T, Glasziou P. Minimal interventions to decrease long-term use of benzodiazepines in primary care: a systematic review and meta-analysis. British Journal of General Practice 2011;61(590):e573-8.
12. Towle I, Adams J. A novel, pharmacist-led strategy to reduce the prescribing of benzodiazepines in Paisley. Pharmaceutical Journal 2006;276(7386):136-138.
13. Johnson C, Thomson A. Prescribing support pharmacists support appropriate benzodiazepine and Z-drug reduction 2008/09 – experiences from North Glasgow. Clin Pharm 2010;3(Supp 1):S5-S6.
14. De Gier NA, Gorgels WJ, Lucassen PL, et al. Discontinuation of long-term benzodiazepine use: 10-year follow-up. Fam Pract 2011;28(3):253-259.