Download QA322 3_ankle oedema with CCBs SO final checked

Medicines Q&As
Q&A 322.3
What are the reported incidences of ankle oedema with different
calcium channel blockers?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
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Date prepared: 18th May 2015
Background
Calcium Channel Blocking agents (CCBs) are a diverse group of drugs which share a common
mechanism of action, and have blood pressure lowering abilities1. Peripheral oedema, including ankle
oedema, is a recognised adverse effect of the calcium channel blocking agents which may limit their
usefulness, particularly in an aging population who are more likely to have co-morbidities2,3,4. Ankle
oedema can range from being mild and unnoticed to severely affecting quality of life 5,6.
The risk of developing ankle oedema whilst using CCB therapy appears to be higher in women, older
patients, those with heart failure, upright postures, and those in warm environments 6,7.
Answer
Mechanism of ankle oedema:
The mechanisms by which CCBs give rise to ankle oedema are not currently understood. Proposed
mechanisms include an increase in capillary pressure, resulting in fluid loss from the capillaries, or by
interference with local vascular control4.
Unlike peripheral oedema caused by fluid retention, CCB-induced oedema appears to be due to
redistribution of fluid from capillaries to interstitial spaces. Oedema caused by CCBs seems
unaffected by diuretic treatment, suggesting it may be due to fluid pooling rather than fluid
retention5,6,8. Oedema occurs despite CCBs possessing inherent diuretic effects 5,6.
As well as these possible mechanisms, CCB therapy blocks reflex increases in precapillary resistance
which occur on standing, further compounding the problem of oedema formation6.
The COHORT study, undertaken in 828 elderly, hypertensive patients, reported that ankle oedema
may have a delayed onset, with its incidence increasing gradually as treatment continues, meaning it
is not likely to be a transient, self limiting effect2,9.
Ankle oedema in patients who have been taking CCBs for a long time may be associated with a
spotty reddish or purple rash, and in some cases hyperpigmentation and discolouration. This is
thought to be due to increases in capillary permeability, leading to leakage of erythrocytes into the
surrounding fluid6,8 .
CCB-related oedema commonly worsens in the evening, and may resolve or improve following the
patient lying down overnight6.
Differences in chemical class:
CCBs are generally classified into dihydropyridines (DHP) and non-dihydropyridines based on their
chemical structure. Whilst ankle oedema is a class effect in all CCBs, there does appear to be
differences in the incidence of ankle oedema between the different classes, with oedema being more
likely with the dihydropyridine agents1,2,6,8. The incidence of ankle oedema has been reported as
ranging from 1-15% in patients treated with DHP agents4. Within the DHP group, it is thought that
those which are more lipophilic, thus stay at the site of action for longer (such as lercanidipine and
lacidipine), may be associated with a lower incidence of ankle oedema2.
Available through NICE Evidence Search at www.evidence.nhs.uk
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The rate of ankle oedema occurring with verapamil therapy is variable. Verapamil increases plasma
volume whilst also reducing vasoconstriction in the lower extremities, similar to amlodipine and
nifedipine10.
Some post-marketing surveillance data has reported a reduced incidence of ankle oedema in patients
treated with diltiazem compared to other CCB agents8.
Ankle oedema also appears to be dose related, and its incidence may exceed 80% in patients taking
long term high doses of DHP agents. However, this association may not occur in an exact doseproportional relationship6,8.
Whilst the longer-acting CCBs generally appear to have fewer adverse effects associated with them
(such as flushing, headache, and palpitations), this is not thought to be the case when considering
ankle oedema5.
Differences in blood pressure lowering ability of different CCB agents do not seem to correlate with
differences in ability to cause ankle oedema7.
Drug
Reported Incidences:
Source
Amlodipine
Nifedipine
Felodipine
Summary of
Product
Characteristics
(SPC)- Amlostin11
Andresdottir MB et
al, 2000 5
Incidence of Ankle Oedema
Dihydropyridine CCBs
Common (>1/100 to <1/10)
Notes
47%
N=32
Lower limb volume measured by water
displacement- may have included
clinically insignificant increases in foot
volume.
Funded by drug manufacturers.
Subjective reporting
Lombardo D et al
19945,12
Per LundJohansen 20037
23%
SPC- Adalat13
Common (>1/100 to <1/10)
Terry RW, 198214
7.7%- general population
10.3% in CHF subgroup
8.2% in concomitant beta
blocker therapy subgroup
11.6%- long term therapy
subgroup.
1.7-32%
Blankfield RP,
200510
MATH and EXACT
trials8,15,16
SPC- Plendil17
33.3%
7.7% at 18 weeks and 8.1% at
20 weeks.
Very Common (>1/10)
N= 44
Post-menopausal hypertensive patients.
Other possible causes of oedema were
excluded from the study population.
Lower limb volume measured by water
displacement- may have included
clinically insignificant increases in foot
volume.
Oedema, including peripheral oedema type not specified.
Review of 3081 patients with angina
pectoris.
Review of 7 papers
XL formulation of nifedipine.
Peripheral oedema
As with other dihydropyridines, dose
dependent ankle swelling can occur in
patients treated with felodipine. “This
results from precapillary vasodilation
Available through NICE Evidence Search at www.evidence.nhs.uk
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Lercanidipine
Isradipine
Lacidipine
Nimodipine
Nicardipine
Diltiazem
Verapamil
Saltiel E et al
198818
Blankfield RP,
200510
SPC- Zanidip19
Per LundJohansen 20037
SPC- Prescal20
STOP-2 trial21
4-30%
and is not related to generalised fluid
retention.”
Review
0-29.6%
Review of 8 papers
Uncommon (>1/1000 <1/100)
9.8%
Blankfield RP,
200510
SPC- Motens22
Andresdottir MB et
al, 20005
7.7-13.9%
Peripheral oedema- type not specified.
N=48
Post-menopausal hypertensive patients.
Peripheral oedema- type not specified.
Randomised, open masked-endpoint
trial
Review of 2 trials.
Blankfield RP,
200510
Lindholm LH et al
19965,23
SPC- Nimotop24
SPC Cardene 20
and 30 mg 25
6%
SPC-Angitil
SR/XL26
Blankfield RP,
200510
SPC (Securon
SR)27
White et al 200128
Blankfield RP
200510
Very common (
25.5%
1/10)
Common (> 1/100 <1/10)
20%
4%
Oedema- type not specified.
N=30
Lower limb volume measured by water
displacement- may have included
clinically insignificant increases in foot
volume.
Funded by drug manufacturers.
Review
Review (via Andresdottir)
Subjective reporting.
Not listed
Peripheral oedema mentioned
but no incidence given.
Non-dihydropyridine CCBs
Very Common (>1/10)
Peripheral oedema
2.6-8.9%
Review of 8 papers
Ankle oedema mentioned but no
incidence given.
2.8%
0.7-13.5%
Review article- n= 1042
General oedema- not just ankle
oedema.
Review of 5 papers
Summary
The potential to cause ankle oedema appears to exist for all calcium channel blocking agents, and it
is caused by increasing capillary pressure leading to leakage of fluids into the surrounding tissues 4.
This occurs in spite of the diuretic nature of some CCB agents5.
Ankle oedema appears to occur more frequently in CCBs from the DHP group, although some agents
such as lacidipine and lercanidipine may cause it less frequently than nifedipine and amlodipine 2,6.
Diltiazem, a non-DHP agent, seems to be associated with the lowest incidence of ankle oedema 8.
Limitations
Reporting of ankle oedema may be subjective, and methods to detect oedema formation were
variable in the trials assessed, from relying on patient self-reporting, to using water displacement
methods. This variation in reporting methods may be responsible for the wide differences in reported
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
incidence of ankle oedema. In addition, inter and intra patient variability in susceptibility may play a
part in the likelihood of oedema formation, so despite reported differences, it is still impossible to
predict which agent may precipitate oedema in individual patients.
Search strategy
Embase
*Calcium channel blocking agent AND *Ankle edema
*Amlodipine AND *Ankle edema
*Nifedipine AND *Ankle edema
*Felodipine AND *Ankle edema
*Lercanidipine AND *Ankle edema
*Isradipine AND *Ankle edema
*Lacidipine AND *Ankle edema
*Nimodipine AND *Ankle edema
*Diltiazem AND *Ankle edema
*Verapamil AND *Ankle edema
*Nicardipine AND *Ankle edema
Medline
*Calcium Channel Blockers AND *Edema
*Amlodipine AND *Edema
*Nifedipine AND *Edema
*Felodipine AND *Edema
Lercanidipine.af AND *Edema
*Isradipine AND *Edema
Lacidipine.af AND *Edema
*Nimodipine AND *Edema
*Nicardipine AND *Edema
eMC & Micromedex
References
1
Frishman WH. Calcium channel blockers: Differences between subclasses. Am J Cardiovasc Drugs
2007; 7(1): 17-23.
2 Messerli FH and Grossman E. Pedal edema- not all dihydropyridine calcium antagonists are created
equal. American Journal of Hypertension. 2002; 15: 1019-1020.
3 Joint Formulary Committee. British National Formulary [online]. London: BMJ Group and
Pharmaceutical Press http://www.medicinescomplete.com/ [Accessed on 03 Nov 2015].
4 Fogari R, Zoppi A, Derose G et al. Effect of valsartan addition to amlodipine on ankle oedema and
subcutaneous tissue pressure in hypertensive patients. Journal of Human Hypertension. 2007; 21:
220–224.
5 Andresdottir M, van Hamersvelt H, van Helden M et al. Ankle edema formation during treatment with
the calcium channel blockers lacidipine and amlodipine: A single-centre study. Journal of
Cardiovascular Pharmacology. 2000; 35: S25-S30.
6 Sica DA. Calcium channel blocker-related peripheral edema: can it be resolved? Journal of Clinical
Hypertension. 2003; 5(4): 291-297.
7 Lund-Johansen P, Stranden E, Helberg S et al. Quantification of leg oedema in post-menopausal
hypertensive patients treated with lercanidipine or amlodipine. Journal of Hypertension. 2002; 10031010.
8 Sirker A, Missouris CG, and Macgregor G. Dihydropyridine calcium channel blockers and peripheral
side effects. Journal of Human Hypertension. 2001: 15; 745-746.
9 Zanchetti A. Emerging data on calcium channel blockers: The COHORT study. Clinical Cardiology.
2003; 26(sII): II-17- II-20.
10 Blankfield R. Fluid Matters in Choosing Antihypertensive Therapy: A hypothesis that the data speak
volumes. JABFP. 2005; 18(2): 113-124.
Available through NICE Evidence Search at www.evidence.nhs.uk
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11
Summary of Product Characteristics- Amlostin (amlodipine). Discovery Pharmaceuticals. Accessed
via MHRA this link on 20th April 2015 [last updated 30/01/2015]
12 Lombardo D, Raimondi F. Efficacy and safety evaluation of lacidipine compared with amlodipine in
mild to moderate hypertensive patients. J Cardiovasc Pharmacol. 1994; 23(S5): S98-100.
13 Summary of Product Characteristics- Adalat (nifedipine). Bayer Pharmaceuticals. Accessed via
http://www.medicines.org.uk/emc/medicine/20901 on 21st April 2015 [last updated on the eMC:
04/08/2015]
14 Terry R. Nifedipine therapy in angina pectoris: Evaluation of safety and side effects. American
Heart Journal. 1982; 104(3): 681-689.
15 Krakoff L, Bravo E, Tuck M et al. Nifedipine gastrointestinal therapeutic system in the treatment of
hypertension. Results of a multicentre trial. The Modern Approach to the Treatment of Hypertension
(MATH) Study group. Am J Hypertens. 1990; 3(12 Pt2): 318S-325S.
16 Toal CB, Mahon WA, Barnes C.Nifedipine gastrointestinal therapeutic system (GITS) for
hypertensive patients in a primary care setting: results of the Extended Release Adalat Canadian Trial
(EXACT). Clin Ther. 1997; 19(5):924-35.
17 Summary of Product Characteristics: Plendil 2.5mg, Plendil 5mg and Plendil 10mg (felodipine).
Astra-Zeneca Pharmaceuticals. Accessed via http://www.medicines.org.uk/emc/medicine/191
on 21st April 2015 [last updated on the eMC: 01/10/2015]
18 Saltiel E, Gray Ellrodt A, Monk J et al. Felodipine: a review of its pharmacodynamic and
pharmacokinetic properties and therapeutic use in hypertension. Drugs. 1988: 36; 387-428.
19 Summary of Product Characteristics: Zanidip 10 mg tablets (lercanidipine). Recordati
Pharmaceuticals. Accessed via
http://www.medicines.org.uk/EMC/medicine/17624/SPC/Zanidip+10+mg+tablets/ on 21st April 2015
[Last updated on the eMC: 29/10/2010]
20 Summary of Product Characteristics: Prescal (Isradipine). Novartis. Accessed via
http://www.medicines.org.uk/EMC/medicine/1311/SPC/Prescal/ on 21st April 2015 [Last updated on
the eMC: 16/06/2014]
21 Hansson L, Lindholm L, Ekbom T et al. Randomised trial of old and new antihypertensive drugs in
elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with
Hypertension-2 study. The Lancet. 1999; 354: 1751-1756.
22 Summary of Product Characteristics: Motens Tablets 2mg (lacidipine). Boehringer Ingelheim.
Accessed via http://www.medicines.org.uk/EMC/medicine/297/SPC/Motens+Tablets+2mg/ on 21st
April 2015 [Last updated on the eMC: 22/01/2016]
23 Lindholm LH, Tcherdakoff P, Zanchetti A. Safety of the calcium antagonist lacidipine evaluated from
a phase III-IV trial database. J Hypertens Suppl. 1996; 14(2):S15-20.
24 Summary of Product Characteristics: Nimotop 30mg Tablets (nimodipine). Bayer Plc. Accessed via
http://www.medicines.org.uk/EMC/medicine/8086/SPC/Nimotop+30mg+Tablets/ on 21st April 2015
[Last updated on the eMC: 17/10/2014]
25 Summary of Product Characteristics: Cardene 20 and 30mg capsules (nicardipine). Astellas
Pharma Ltd. Accessed via http://www.medicines.org.uk/emc/medicine/5885 on 13/05/15 [last updated
on the eMC 12/01/16
26 Summary of Product Characteristics: Angitil (diltiazem) SR/XL 90,120,180,240 and 300 mg
Prolonged Release Capsules. Chiesi Ltd. Accessed via
http://www.medicines.org.uk/EMC/medicine/21318/SPC/Angitil+SR+XL+90%2c120%2c180%2c240+
and+300+mg+Prolonged+Release+Capsules/ on 21st April 2015 [last updated on the eMC:
14/08/2015]
27 Summary of Product Characteristics: Securon SR (verapamil). Abbott Laboratories. Accessed via
http://www.medicines.org.uk/EMC/medicine/20808/SPC/Securon+SR/ on 21st April 2015 [Last
updated on the eMC: 16/04/2015]
28 White W, Johnson M, Anders R et al. Safety of controlled-onset extended-release verapamil in
middle-aged and older patients with hypertension and coronary artery disease. American Heart
Journal. 2001; 142: 1010-1015.
Available through NICE Evidence Search at www.evidence.nhs.uk
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Quality Assurance
Prepared by
Vincent Cassidy (based on earlier work by the same author and Hayley Johnson),
Regional Drug & Therapeutics Centre, Newcastle upon Tyne
Date prepared
18th May 2015
Checked by
Charity Murefu, Regional Drug & Therapeutics Centre, Newcastle upon Tyne
Date of check
3rd November 2015
Q&A Lead Final Check by
Samantha Owen, Southampton Medicines Advice Service, University Hospital Southampton NHS
Foundation Trust
Available through NICE Evidence Search at www.evidence.nhs.uk
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