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					PRESCRIBING and
CLINICAL EFFECTIVENESS
NEWSLETTER        Supporting the
                                             Derbyshire Health Community
Volume 9: Issue 1                                                                                  April 2010

Further in this issue      Page 2        Combinations of antihypertensive drugs
                                         Improving statin adherence
                           Page 3        Interactions with herbal remedies
                           Page 4        Treatment of depression, Effectiveness of antidepressant drugs
                           Page 5        Tamoxifen and SSRIs
                           Page 6        Bath emollients for atopic eczema
                           Page 7        PPIs and fractures, ACEIs plus ARBs
                           Page 8        ARBs and angioedema
JAPC Update
The Joint Area Prescribing Committee (JAPC) is a countywide group covering NHS Derbyshire County and NHS
Derby. It provides recommendations on drugs and medicines management issues.
RED drugs are those where prescribing responsibility lies with a hospital consultant or a specialist. AMBER drugs
are those that are initiated within a hospital/specialist setting but are suitable for shared care with a GP under a
shared care agreement. GREEN drugs are regarded as suitable for primary care prescribing. BROWN drugs are
those that JAPC does not recommend for use, except in exceptional circumstances, due to lack of data on safety,
effectiveness, and/or cost-effectiveness.

The most recent updates are in the table below; the full list is available at
http://www.derbyshiremedicinesmanagement.nhs.uk/home
The guidelines, formulary chapters, newsletters, etc can also be found via this link.

 Drug                                                  Date considered      Decision
 Certolizumab                                          April 2010           RED
 Ertapenem                                             April 2010           RED
 Intanza                                               April 2010           BROWN
 Ganciclovir eye gel                                   April 2010           RED
 Levofloxacin eye drops                                April 2010           RED
 Thalidomide                                           April 2010           RED

Generic clopidogrel
The price of generic clopidogrel has dropped significantly in the April edition of the Drug Tariff. It now costs
£132.62 for a year’s supply. Compare this with £433.62 for branded clopidogrel (Plavix) and £619.98 for
prasugrel. As the clopidogrel preparations are deemed to be bioequivalent, JAPC recommends that prescribers
should prescribe generically for all indications and prescribe the most cost-effective salt once that option is
available on the prescribing system.

Another negative aspirin in primary prevention study
The results of the Aspirin for Asymptomatic, Atherosclerosis trial have been published1. In this double-blind
randomised trial, 3,350 people aged 50 to 75 years without clinically evident CV disease but with a screening-
detected ankle brachial index of 0.95 or less, were randomly assigned to receive aspirin EC 100mg daily or
placebo.

After a mean follow-up of 8.2 years, aspirin was no more effective than placebo at reducing the primary endpoint
of a fatal or non-fatal coronary event, stroke, or revascularisation. It also had no significant effect on any of the
secondary endpoints.
          The Newsletter is produced by Peter Burrill - Specialist Pharmaceutical Adviser for Public Health
                                    peter.burrill@derbyshirecountypct.nhs.uk
The accompanying editorial2 states that based on this trial and similar studies, aspirin appears to have marginal
benefits for reducing initial cardiovascular events when used for patients without clinically evident CV disease and
is associated with higher rates of bleeding events in these patients.

   1.   JAMA 2010; 303: 841-8
   2.   JAMA 2010; 303: 880-2

Combinations of antihypertensive drugs
An epidemiological study suggests that people with hypertension taking a diuretic plus a calcium-channel blocker
(CCB) may have a higher risk of myocardial infarction (MI) than those taking diuretics with beta-blockers or with
ACE-inhibitors/angiotensin receptor blockers (ARB)1. Risk of stroke was similar.

Low dose diuretics are a mainstay of antihypertensive treatment and are recommended as the first-line therapy for
many patients in both US and UK guidelines. There is no controlled trial evidence, however, on the optimum
second-line drug. The authors of this report therefore carried out a case-control study using data from a US
Health Maintenance Organisation to compare clinical outcomes in patients aged 30 - 79 years with hypertension
who were treated with low-dose diuretic plus another commonly-used antihypertensive drug. Cases were patients
with hypertension who had a diagnosis of incident fatal or non-fatal MI between January 1989 and December
2005 or a fatal or non-fatal stroke between July 1989 and December 2005 (excluding events that were
complications of a medical or surgical procedure). Controls were treated hypertensive patients with no MI or
stroke and were selected in the ratio between 2:1 to 3:1. Patients with existing cardiovascular morbidity or
diabetes were excluded to minimise confounding by indication. Primary outcome was MI or stroke.

There were 1,305 eligible patients identified who were treated with a two-drug anti-hypertensive regimen; 211 who
had a first MI, 142 who had a first stroke, and 952 controls. Of these, 629 were treated with diuretics plus beta-
blockers, 273 with diuretics plus CCB, and 403 with diuretics plus ACE-inhibitors or ARB. As a result of the
exclusion criteria, they were a relatively low-risk population.

Patients being treated with diuretics plus CCB had a higher risk of MI than those being treated with diuretic plus
beta-blocker (adjusted odds ratio (OR) 1.98 95% CI 1.37 to 2.87). Their risk of stroke however, was similar (OR
1.02, 95% CI 0.63 to 1.64). The risks of MI and stroke in those treated with diuretics plus ACE-inhibitors or ARB
were not statistically significantly different to those on diuretic plus beta-blocker.

The authors conclude that in this patient population, antihypertensive drug treatment including a diuretic plus CCB
was associated with a higher risk of MI than treatments including diuretic plus beta-blocker or ACE-inhibitor/ARB.
They note that as an observational study, the difference may be due to unmeasured confounding, however they
note that there is a plausible explanatory mechanism and suggest that a randomised controlled trial is needed to
identify the optimum second-line drug to be added to low-dose diuretic for hypertension.

   1.   BMJ 2010; 340: c103

Improving statin adherence
A simulation study using trial data suggests that improving adherence to statins among those currently considered
eligible for treatment would prevent more cardiovascular deaths than lowering the present treatment threshold1.

Statins with patient-orientated outcome evidence are effective in lowering blood cholesterol levels and reduce the
risk of cardiovascular disease in those who take them. Effectiveness in practice is lower than that in trials,
however, because at least half those people started on the drugs will have stopped taking them within five years.
While discussions on improving outcomes have mostly been related to lowering treatment thresholds, thus
increasing the number of people receiving the drugs, it is possible that similar benefits could be gained by
improving adherence in those already eligible for them. The aim of this simulation study was to investigate the
potential effects of the two strategies.

The authors searched the literature for randomised controlled trials of statins that included information on
adherence, and for any community-based studies of statin adherence. They used data from these studies in a
model based on patient data from a large prospective cohort study recruited between 1990 and 1994 (the
Melbourne Collaborative Cohort Study) that included information on participants’ cardiovascular status and the

                                                         2
data required to calculate their cardiovascular risk status using the Framingham equations. These enabled
estimation of the population level benefits of three scenarios: 1) baseline, using current NICE treatment threshold
(> 20% risk of CVD disease over 10 years) and projected adherence of 50%; 2) enhanced adherence to 75% and
3) a lowered treatment threshold calculated to result in the same number of people taking statins as the enhanced
adherence option (about 15.5% 10-year risk). Outcomes were risk of incident cardiovascular disease (CVD) and
death due to CVD.

There were 41,141 people (17,049 men) in the Melbourne study cohort, with a mean age of 55 at baseline (range
25-75). After exclusions (2,485 with existing CVD, 388 with missing data), there were 38,268 subjects available
for analysis. In this population without statin treatment, the expectation over 10 years would be 5,390 onsets of
CVD and 710 CVD deaths. Just under a quarter (24%, 9,279/38,268) would have a 10-year risk > 20% and would
thus be eligible for statin treatment. In the baseline scenario, half the 9,279 eligible under NICE guidelines were
considered to be adherent to statins and in this group 174 CVD onsets and 70 CVD deaths were averted.

Both alternative scenarios increased the numbers of events avoided. In the lowered treatment threshold scenario,
6,991 were assigned to be adherent, resulting in an estimated additional 70 CVD onsets and 18 CVD deaths
being averted. In the enhanced-adherence scenario, however, 6,971 subjects were assigned to be adherent to
statin medication, resulting in an additional 91 CVD onsets and 37 CVD deaths being averted. In sensitivity
analyses, the gain from improving adherence was robust to a range of plausible alternative values of baseline
adherence and improvement in adherence, and degree of cholesterol lowering.

The authors conclude that according to their model, twice as many CVD deaths would be prevented by improving
adherence in patients currently eligible for statin treatment as would be prevented by lowering the treatment
threshold to produce a similar number of people taking the drugs. While the model did not include cost-
effectiveness analyses, the result implies that the incremental cost-effectiveness of the improved adherence
strategy would also be approximately double. Overall, they comment that failure to take adherence levels into
account in chemoprevention strategies leads to overestimation of benefits. Improving adherence in those at
higher risk gives greater benefits than extending prevention to those at lower risk, and more work is therefore
needed on ways to improve long-term adherence.

1. J Epidemiol Community Health 2010; 64: 109-13

Interactions with herbal remedies
Herbal remedies are perceived as being natural and therefore safe by the general public, but many have adverse
effects and sometimes these can produce life-threatening consequences. Most patients do not readily disclose
their use of herbal remedies to their healthcare providers and healthcare professionals may not routinely ask
about such use. As a result, dangerous herb-drug interactions may be missed. An article in the Journal of the
American College of Cardiology has reviewed the use of herbal products and potential interactions in patients with
CV diseases1.

St. John’s wort is highlighted as a herbal product that could potentially result in serious adverse reactions because
of its effect on drug metabolism; it induces the hepatic cytochrome P450 system, particularly CYP3A4, an enzyme
involved in oxidative metabolism of more than 50% of all prescription medications, including some anti-
arrhythmics, statins, calcium-channel blockers, irbesartan, metoprolol, carvedilol, and importantly warfarin.

The paper provides a table of herbal products to avoid in patients with CV diseases. Here are some key entries.
This list is not exhaustive.

Herb                                          Cardiac adverse effect of interaction
Alfalfa                                       Increases bleeding risk with warfarin
Aloe Vera                                     Hypokalaemia causing digitalis toxicity and arrhythmia
Angelica (dong quai)                          Increases bleeding risk with warfarin
Garlic                                        Increases bleeding risk with warfarin
Ginger                                        Increases bleeding risk with warfarin
Ginkgo                                        Increases bleeding risk with warfarin, aspirin, or Cox-2 inhibitors.
Ginseng                                       Increases blood pressure. Decreases effects of warfarin.
Grapefruit juice                              Increases effects of statins and CCBs.
                                                              3
Green tea                               Decreases effects of warfarin (contains vitamin K).
Kelp                                    Increases effects of antihypertensive and anticoagulant agents.
St John’s wort*                         Increases heart rate and blood pressure (with MAOI). Decreases digoxin
                                        concentration.
Yohimbine                               Increases heart rate. Increases or decreases blood pressure.
* avoid use with warfarin – see JAPC anticoagulation guideline

   1.   JACC 2010; 55: 515-25

Treatment of depression
NICE clinical guideline (CG90) on the treatment and management of depression in adults includes the following
recommendations:

    •   Low-intensity psychosocial interventions – for people with persistent subthreshold depressive
        symptoms or mild to moderate depression, consider offering one or more of the following interventions,
        guided by the person’s preference: individual guided self-help based on principles of cognitive behavioural
        therapy (CBT), computerised CBT, or a structured group physical activity programme.
    •   Drug treatment – do not use antidepressants routinely to treat persistent subthreshold depressive
        symptoms or mild depression, but consider them for people with a history of moderate or severe
        depression, or initial presentation of subthreshold depressive symptoms that have been present for a long
        period (typically at least 2 years), or subthreshold depressive symptoms or mild depression that persist(s)
        after other interventions.
    •   Treatment for moderate or severe depression – for people with moderate or severe depression,
        provide a combination of antidepressant medication and a high intensity psychological intervention, such
        as CBT.
    •   Continuation and relapse prevention – if a person has benefited from taking an antidepressant they
        should be encouraged to continue it for at least 6 months after remission.

NICE now recommends diagnosis according to DSM-IV criteria. The review carried out for the NICE guideline
assessed the evidence for escitalopram and duloxetine▼ for the first time. However, the overall conclusion was
that antidepressants have largely equal efficacy. Choice should, therefore, largely depend on side-effect profile,
patient preference and previous experience of treatments, propensity to cause discontinuation symptoms and
safety in overdose. Potential interactions with concomitant medications or physical illness are also important to
consider when choosing an antidepressant. A generic selective serotonin reuptake inhibitor should normally
be chosen. Both dosulepin and St John’s wort are not recommended for depression. Moreover, NICE
advises that healthcare professionals should not recommend use of St John’s wort (for example, bought
over the counter or on the internet).

SIGN recently published a guideline on the non-pharmaceutical management of depression in adults. The quick
reference guide is available at www.sign.ac.uk/pdf/qrg114.pdf This also makes a statement about Hypericum (St
John’s wort), recommending that healthcare professionals should not advise its use due to lack of standardisation
of dose and the risk of interactions with several common medications, including the contraceptive pill. It adds that
where individual patients are using St John’s wort for treatment of depression, the GP should facilitate full
consideration of potential drug interactions.

Effectiveness of antidepressant drugs
A meta-analysis of patient-level data has found that the benefits of antidepressant drugs in comparison with
placebo rise with increasing severity of depression, and may be minimal or non-existent, on average in patients
with mild or moderate symptoms1.

Previous analyses have indicated that the therapeutic effect of antidepressive drugs is greater in patients with
more severe depression; however these have not included many patients with less severe depression and also
had other limitations. The authors of this study aimed to clarify the effect by ensuring inclusion of patients with a
range of baseline severity, by excluding studies that excluded some placebo responders with a placebo washout
period, and by analysing patient-level data. They carried out a literature search for randomised, placebo-


                                                          4
controlled trials of antidepressive drugs in out-patient populations with a range of depression severity, without a
placebo washout period, and where original patient-level data were available. Other criteria included at least six
weeks active vs. placebo treatment, and Hamilton Depression Rating Scale (HAM-D) scores at baseline and end
of treatment. The analysis studied the relationship between baseline symptom severity and subsequent symptom
change from intake to the end of acute treatment.

Patient-level data were available for six studies (n=718), which were thus used for the analysis. Three of the
included studies used imipramine and three paroxetine; study quality was generally good, and the range of mean
baseline HAM-D scores was 14 to 24. The sample was divided into 3 groups: mild to moderate depression (HAM-
D score of 18 or less); severe (19 to 22); and very severe (23 or greater).

Analysis found a significant interaction between baseline symptom severity and the change in symptoms with
treatment. Plotting regression lines for the relation between initial severity and change in symptoms showed a
positive effect for both drug and placebo, however the slopes of the two lines were different: they converged at the
lower end of symptom scores and the size of the difference between the lines increased as symptom score
increased. For illustrative purposes, the symptom scores were divided into mild to moderate, severe, and very
severe using standard criteria, and numbers-needed-to-treat (NNT) compared to placebo calculated for the three
categories. These were 16, 11, and 4 respectively. Tests by drug class found no significant difference between
imipramine and paroxetine.

The authors also estimated the point at which the drug-placebo difference crossed the thresholds of clinical
significance defined for antidepressive treatment by NICE. These thresholds were met where the baseline HAM-
D scores were between 25 and 27.

Based on their analysis, the authors conclude that the efficacy of antidepressive drug treatment varies with
baseline symptom severity. For patients with less severe depression, the true drug effect was limited whereas for
patients with very severe symptoms drugs were markedly superior to placebo. They note that there are limitations
to their analysis, but comment that its results are consistent with previous work; they emphasise that their analysis
applies only to acute, not chronic and maintenance therapy.

1. JAMA 2010; 303: 47-53

Tamoxifen and SSRIs
Appendix 1 (interactions) of BNF 58 states that metabolism of tamoxifen to active metabolite is possibly inhibited
by duloxetine, fluoxetine and paroxetine, so concomitant use should be avoided. A recently published population
based cohort study concludes that paroxetine use during tamoxifen treatment is associated with an increased risk
of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of
tamoxifen in women with breast cancer1.

Tamoxifen is highly effective in the treatment of breast cancer, however it is now known that it acts as a prodrug
and its effects are due to conversion to active metabolites: the most important of these is endoxifen. The
conversion relies mainly on CYP2D6, thus drugs that inhibit this enzyme could potentially reduce the efficacy of
tamoxifen (which is also reduced in the 7% of so of the population who lack the functional enzyme). The most
widely used drugs that inhibit CYP2D6 are some of the SSRI antidepressants: this population-based retrospective
cohort study aimed to determine whether use of any SSRI concurrently with tamoxifen affected its efficacy.

The study population was identified using healthcare databases from Ontario, Canada, and comprised female
residents who were aged over 66 and who started tamoxifen therapy for the first time between January 1993 and
December 2005 inclusive. Patients were followed up from the index date until death from breast cancer or the
end of the study period (31/1/07). Those who were prescribed a single SSRI antidepressant or venlafaxine during
tamoxifen treatment were identified, and their outcomes were evaluated according to time on SSRI therapy. The
primary outcome was death from breast cancer.

Over the study period, there were 24,430 women who started taking tamoxifen; 7,489 (30.6%) were prescribed an
antidepressive drug and 2,430 of these were available for analysis after exclusions (received no SSRI or multiple
SSRI, had poor tamoxifen adherence, or unknown cause of death). Most started tamoxifen within a year of breast

                                                         5
cancer diagnosis, at a median age of 74 years, and median duration of use was 4.0 years. Paroxetine was the
SSRI most commonly prescribed, followed by sertraline, citalopram, venlafaxine, fluoxetine, and fluvoxamine.

By the end of the follow-up period, 1,074 (44.2%) had died, with breast cancer recorded as the primary cause of
death in 374 (15.4%). Those taking paroxetine concurrently with tamoxifen had an increased risk of death; after
adjustment for confounding factors, absolute increases of 25%, 50%, and 75% in the proportion of time on
tamoxifen that overlapped with use of paroxetine were associated with relative increases of 24%, 54%, and 91%
in the risk of death from breast cancer, respectively. The authors estimated that treatment with paroxetine for
41% of tamoxifen therapy (the median in the study) could result in one additional breast cancer death at 5 years
for every 20 women so treated. There was no significant increase in risk of death due to breast cancer associated
with use of any other SSRI.

The authors conclude that concurrent use of paroxetine and tamoxifen is associated with an increased risk of
death, directly related to duration of overlapping use. They suggest that this is consistent with the hypothesis that
paroxetine can reduce or abolish the metabolic activation of tamoxifen via inhibition of CYP2D6. They note that
paroxetine, unlike some other compounds, is an irreversible CYP2D6 inhibitor. The study has some limitations,
but the authors suggest that these were unlikely to negate the results. They also note the lack of observed effect
with fluoxetine, a known strong inhibitor of CYP2D6: they comment that this may have been due to the small
numbers on this drug, and emphasise that it should not be taken to conclude safety with fluoxetine.

The accompanying editorial2 suggests that for safety reasons, co-prescription of fluoxetine and tamoxifen should
be avoided until additional evidence becomes available. The authors state that the best option in women who
take tamoxifen is to avoid prescribing strong CYP2D6 inhibiting SSRIs (such as paroxetine or fluoxetine) and to
consider instead drugs with low potential to inhibit CYP2D6 (such as citalopram).

        Key point: avoid co-prescribing paroxetine or fluoxetine with tamoxifen


   1.    BMJ 2010; 340: c693
   2.    BMJ 2010; 340: c782

Bath emollients for atopic eczema
Regular topical application of an emollient cream or ointment is key in the management of patients with atopic
eczema and is thought to help the skin maintain an effective defensive barrier, which is defective in atopic
eczema. Support for such treatment comes from one (non-blinded) randomised controlled trial, which found that
regular application of emollients direct to the skin reduced the amount of topical corticosteroid cream needed for
atopic eczema in infants1. Long clinical experience also suggests that directly applied emollients are safe and
effective in atopic eczema.

People with atopic eczema are commonly also advised to use an emollient substitute for soap (such as aqueous
cream or emulsifying ointment), as soap can irritate the skin (as can bubble bath preparations); patients are also
often prescribed a bath emollient to add to their bath water. Bath emollients typically consist of liquid paraffin plus
another emollient (usually wool fat or isopropyl myristate); a few also contain an antimicrobial drug.

Some prescribers recommend bath emollients to avoid use of bubble bath preparations. Some believe that using
a bath emollient is an easy way to apply an emollient to a large area of skin, particularly for children, who may not
cooperate with having topical emollients applied frequently. Also, some treatment guidelines argue that complete
emollient therapy (a combination of creams, ointments, bath emollients, and soap substitutes) will provide
maximal effect. Of note, the NICE guideline on atopic eczema in children suggests the additional use of bath
emollients for some children “to ensure that adequate amounts of emollient are absorbed into their skin.” These
influences have prompted very common use of bath emollients for atopic eczema1.

An article in the BMJ has explored the evidence for the use of bath emollients in eczema1. This is their
conclusion:

“No published randomised controlled trials have specifically assessed the clinical efficacy of bath emollients in
atopic eczema. Also, we are not aware of any longstanding clinical experience of benefit from bath emollients to
                                                           6
match that for directly applied emollients. The quantities of emollient deposited on the skin during bathing are
likely to be far lower than with directly applied emollients. These points highlight the weakness of the case for
using bath emollients.

Additionally, we found no published evidence that ‘complete emollient therapy’ has a ‘maximal effect’. Moreover,
the unproved concept of ‘complete emollient therapy’ has fostered assumptions that each of the individual
components (including bath emollients) contributes to a worthwhile benefit, despite the absence of confirmatory
data. On current evidence, bath emollients could be offering little or no benefit. If so, people who use them in
place of directly applied emollients are unknowingly receiving substandard emollient therapy.”

1. BMJ 2010; 340: 361-2

PPIs and fractures
Can PPIs increase the risk of osteoporotic fractures? A publication from the Newcastle Regional Drug and
Therapeutics Centre attempts to answer this question1.
Summary:
Recent case-control studies have suggested an association between proton pump inhibitor (PPI) use and fracture
risk. This is potentially important, as millions of people worldwide use these medications. At present there is no
evidence that PPI therapy should be discontinued when it is used for an appropriate indication, but the doses and
durations of therapy used should be kept to a minimum. There are no data indicating differences in risk between
individual PPIs. Recipients should be advised to maintain an adequate dietary intake of calcium during long term
PPI therapy. This can be supplemented with calcium salts as required.

Practice points:
The research to date identifies a probable increased risk of fracture in patients taking PPIs for longer than one
year, although the absolute risk to the individual patient remains low.
   • The clinician should weigh the proven benefits of PPI use against the potential risk of osteoporotic fracture.
   • Long term PPI therapy should be prescribed at the lowest dose for the shortest time necessary to achieve
        the desired treatment outcomes.
   • Patients using long-term (>1 year) PPI therapy should be advised to maintain an adequate calcium intake,
        which may involve a calcium supplement in some patients.

1. Safe Medication Use. Regional Drug & Therapeutics Centre, Wolfson Unit. December 2009.

ACEIs plus ARBs
Three UKMi Q & As attempt to answer the question what is the rationale and evidence for combining angiotensin
converting enzyme inhibitors with angiotensin II receptor blockers in renal disease1, heart failure2, and vascular
diseases and hypertension3.

Renal disease summary
   • The Renal Association advises that the combination of an ACE inhibitor and ARB should only be initiated
      under specialist supervision in patients with renal disease.
   • Clinical evidence suggests that dual blockade of the renin-angiotensin system may be beneficial in the
      management of macroalbuminuria/proteinuria in diabetic and non-diabetic renal disease.
   • Despite more trials there is less convincing evidence for dual blockade in patients with microalbuminuria.
   • There is suggestion that dual blockade may give greater reductions in albuminuria for those patients with
      prevailing higher levels of albuminuria.
   • The optimal combination of ACE inhibitors and ARBs still remains to be defined.
   • Further study is needed on major renal outcomes to establish the benefits of combination treatment.
   • So far the studies investigating microalbuminuria are small short term studies and considering that renal
      disease is a chronic condition, studies with longer follow-up are needed.

Heart failure summary
   • Candesartan and valsartan are licensed to be used together with an ACE inhibitor for heart failure.
   • Based on the results of the CHARM-Added study, the addition of candesartan to an ACE inhibitor leads to
       a further reduction in cardiovascular death.
                                                                7
   •    Based on the results of the Val-HeFT study, valsartan in addition to an ACE inhibitor is no more effective in
        reducing mortality than an ACE inhibitor alone.
   •    The risk of adverse events, especially, renal dysfunction and hyperkalaemia may increase with
        combination therapy.
   •    The addition of ARB to an ACE inhibitor can be considered in heart failure patients if standard therapy has
        already been optimised.
   •    Evidence suggests, the addition of an ARB to an ACE inhibitor is beneficial in heart failure patients not
        taking beta-blockers.
   •    Further evidence is needed before the combination can be routinely recommended.

The JAPC heart failure guideline recommends that the combination of ACEI, beta-blocker, and ARB may be
considered for persistently symptomatic patients – to be initiated only by a specialist.

Vascular disease/hypertension summary
To date there is no convincing evidence to support the use of an ACE inhibitor in combination with an ARB in
patients with vascular diseases such as cardiovascular disease or diabetes mellitus (high risk vascular patients)
and post MI patients. Similarly the available evidence indicates no additional benefit of combining an ACE
inhibitor with an ARB for patients with mild to moderate hypertension.

   1.   UKMi Q&A 295.1   2. UKMi Q&A 296.1    3. UKMi Q&A 297.1

ARBs and angioedema
Angioedema is a vascular reaction characterised by non-pitting oedema of the dermis and subcutaneous fat. Any
area of the body may be involved but most common sites are the tongue, lips, throat, nose or other parts of the
face, extremities, genitalia and viscera. Angioedema of the upper respiratory tract can result in serious acute
respiratory distress, airway obstruction and death. Drugs are among the multiple precipitating factors and
angioedema is a known adverse effect of angiotensin converting enzyme (ACE) inhibitors.

The onset of angioedema has usually been within hours and the risk is highest within the first month of ACE
inhibitor use. However, it can occur many months or years after starting treatment. It may also occur episodically
with long symptom-free intervals. Angioedema with ACE inhibitors was first reported in 1980 and since then there
has been an increase in reports. The estimated incidence of ACE inhibitor-induced angioedema is 0.1 - 0.2%.
However, as ACE inhibitors are given long term, and patients may develop angioedema any time during therapy,
the risk may be as high as 1% for patients after 10 years’ treatment.

Can an angiotensin II receptor blocker (ARB) be used if angioedema has occurred with an ACE inhibitor? A UKMi
Q&A attempts to answer that question1.
Summary:
   • Angioedema, a known adverse effect of ACE inhibitors is reported to occur in 0.1 - 0.2% of patients.
      However, as ACE inhibitors are given long term and patients may develop angioedema any time during
      therapy; the risk may be as high as 1% for patients after 10 years’ treatment.
   • The exact mechanism of angioedema associated with ACE inhibitors has not been determined. The most
      widely held theory is that it results from the reduced inactivation of bradykinin by ACE inhibitors.
   • Because ACE inhibitor-induced angioedema is thought to be related to accumulation of bradykinin, it was
      assumed that ARBs would not cause this reaction. However this does not seem to be the case.
   • The incidence of angioedema in patients receiving ARBs is uncertain but appears to be lower than in
      patients receiving ACE inhibitors.
   • There is limited evidence to suggest that a significant number of patients who develop angioedema while
      receiving ARBs have previously experienced angioedema during ACE inhibitor therapy.
   • The incidence of angioedema in patients switched to an ARB following ACE-inhibitor induced angioedema
      has been described mainly in case reports and case series, with an incidence ranging from less than 10%
      to greater than 50%.
   • As angioedema is potentially life threatening, ARBs should be used with extreme caution in patients who
      have previously experienced angioedema while receiving ACE inhibitors. The risk of recurrent
      angioedema should be discussed carefully with the patient.
   1. UKMi Q&A 292.1
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