Medicines Q&As
Q&A 322.1
What are the reported incidences of ankle oedema with different
calcium channel blockers?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date Prepared: 19th May 2011
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 life5,6.
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 environments6,7
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 calcium channel
blocking agents appears unaffected by administration of diuretics, suggesting it may be due to fluid
pooling rather than fluid retention5,6,8. Oedema occurs despite CCBs possessing inherent diuretic
effects5,6.
As well as the above 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
petechial rash and in some cases hyper pigmentation and discolouration. This is thought to be due to
increases in capillary permeability, leading to leakage of erythrocytes into the surrounding fluid 6,8 .
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 appears to be a class effect in all CCBs, there does appear
to be differences in the incidence of ankle oedema between the different classes, with oedema
appearing to be more likely with the dihydropyridine agents 1,2,6,8. 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 “membranophilic” (such as lercanidipine and lacidipine), may be
associated with lower incidence of ankle oedema 2.
From the National Electronic Library for Medicines. www.nelm.nhs.uk
1
Medicines Q&As
The rate of ankle oedema occurring with verapamil therapy is variable. Verapamil increases plasma
volume whilst also reducing vasoconstriction in the lower extremities, similarly 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 oedema 5.
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
Very Common >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
Terry RW, 198214
Very Common > 1% to <10%
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
Saltiel E et al
198818
33.3%
7.7% at 18 weeks and 8.1% at
20 weeks
No specific incidence reported
4-30%
N= 44
Postmenopausal 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- not specified into what type
Review of 3081 patients with angina
pectoris.
Review of 7 papers
XL formulation of nifedipine
“As with other calcium antagonists ankle
swelling, resulting from precapillary
vasodilation, may occur. The degree of
ankle swelling is dose related.”
Review
From the National Electronic Library for Medicines. www.nelm.nhs.uk
2
Medicines Q&As
0-29.6%
Review of 8 papers
Lercanidipine
Blankfield RP,
200510
SPC- Zanidip19
Uncommon- (>1/1000 <1/100)
9.8%
Isradipine
Per LundJohansen 20037
SPC- Prescal20
STOP-2 trial21
25.5%
Blankfield RP,
200510
SPC- Motens22
7.7-13.9%
Peripheral oedema- not specified into
what type
N=48
Post menopausal hypertensive patients.
Peripheral oedema- not specified into
what type.
Randomised, open masked-endpoint
trial
Review of 2 trials
Andresdottir MB et
al, 20005
20%
Blankfield RP,
200510
Lindholm LH et al
19965,23
SPC- Nimotop24
6%
Lacidipine
Nimodipine
Diltiazem
Verapamil
SPC-Angitil
SR/XL25
Blankfield RP,
200510
SPC (Securon
SR)26
White et al 200127
Blankfield RP
200510
Very common (
1/10)
Common> 1/100, <1/10
4%
Oedema
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
Non-dihydropyridine CCBs
Very Common (>1/10)
Peripheral oedema
2.6-8.9%
Review of 8 papers
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 is
caused by increasing capillary pressure leading to leakage of fluids into the surrounding tissues4. 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, appears 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
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.
Disclaimer
 Medicines Q&As are intended for healthcare professionals and reflect UK practice.
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Medicines Q&As
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Quality Assurance
Prepared by
Vincent James Cassidy and Hayley Johnson,
Regional Drug and Therapeutics Centre, Newcastle upon Tyne
Date Prepared
19th May 2011
Checked by
Sahima Rahman, Regional Drug and Therapeutics Centre, Newcastle upon Tyne
Date of check
29th June 2011
Search strategy
Embase
*Calcium channel blocking agent AND *Ankle oedema
*Amlodipine AND *Ankle oedema
*Nifedipine AND *Ankle oedema
*Felodipine AND *Ankle oedema
*Lercanidipine AND *Ankle oedema
*Isradipine AND *Ankle oedema
*Lacidipine AND *Ankle oedema
*Nimodipine AND *Ankle oedema
*Diltiazem AND *Ankle oedema
*Verapamil AND *Ankle oedema
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
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 61 [online] 2011 ed. London: British Medical
Association and Royal Pharmaceutical Society http://www.medicinescomplete.com/ [Accessed on 11
Apr 2011].
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
4
Fogari R, Zoppi A, Derose G et al. Effect of valsartan addition to amlodipine on ankle oedema and
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5 Andresdottir M, van Hamersvelt H, van Helden M et al. Ankle edema formation during treatment with
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7 Lund-Johansen P, Stranden E, Helberg S et al. Quantification of leg oedema in post-menopausal
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8 Sirker A, Missouris CG, and Macgregor G. Dihydropyridine calcium channel blockers and peripheral
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From the National Electronic Library for Medicines. www.nelm.nhs.uk
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