About ankle oedema
Peripheral oedema, including ankle oedema, is a recognised adverse effect of calcium channel blockers (CCBs). This may affect compliance but also limit their usefulness, particularly in an aging population who are more likely to have co-morbidities.
The risk of developing ankle oedema whilst on a CCB appears to be higher in women, older patients, those with heart failure, upright postures, and those in warm environments.
Ankle oedema can range from being mild and unnoticed to severely affecting quality of life.
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.
CCB-related oedema commonly worsens in the evening, and may resolve or improve following the patient lying down overnight.
The COHORT study of 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 effect.
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 and leakage into interstitial areas, or
- by interference with local vascular control
- blocking reflex increases in precapillary resistance which occur on standing, compounding oedema formation
Unlike peripheral oedema caused by fluid retention, CCB-induced oedema appears to be due to redistribution of fluid from capillaries to interstitial spaces.
It seems unaffected by administration of diuretics, supporting the idea that it may be due to fluid pooling rather than fluid retention.
Oedema occurs despite CCBs possessing inherent diuretic effects.
Factors affecting incidence
Differences in chemical class
CCBs are generally classified into 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.
Oedema appears to be more likely with the dihydropyridine agents.
The incidence of ankle oedema has been reported as ranging from 1 to 15% in patients treated with DHP agents. There are thoughts suggesting more lipophilic agents, such as lercanidipine and lacidipine, may be associated with lower incidence of ankle oedema.
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 nifedipine.
Some post-marketing surveillance data has reported a reduced incidence of ankle oedema in patients treated with diltiazem compared to other CCB agents.
Ankle oedema is 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 dose-proportional relationship.
Duration of action
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.
Effect on blood pressure
Differences in blood pressure lowering ability of different CCB agents do not seem to correlate with differences in ability to cause ankle oedema.
Treatment of ankle oedema will depend on the severity and other patient factors. Mild oedema that is not troublesome to the patient does not require specific intervention.
Whilst ankle oedema associated with CCBs is rarely clinically serious, it may significantly reduce adherence to these potentially useful agents.
Elevation of legs when in a prone position, or graduated compression stockings, may be an option in some patients with mild oedema. However, there is little evidence to suggest these methods may be effective in reducing oedema.
As ankle oedema is dose-related (although not necessarily in a dose-proportional manner), reducing the dosage of a CCB may lead to a reduction in severity of ankle oedema.
Switching to another CCB
Switching to another CCB class may reduce ankle oedema, although current evidence on the success rates of this strategy are conflicting.
- switching from a dihydropyridine (DHP) agent to a non-dihydropyridine agent if clinically suitable, such as verapamil, which may lead to resolution of the ankle oedema
- switching to a third generation dihydropyridine, such a lercanidipine, which has a lower reported incidence of ankle oedema
Angiotensin Converting Enzyme Inhibitors (ACEi)
It has been demonstrated in several trials that adding an ACEi to a CCB reduces the incidence of ankle oedema.
The mechanism by which this occurs is not currently known. It may be due to the dilation of venous capacitance vessels, which may then lead to a reduction in capillary hypertension and therefore leakage of fluid into the surrounding tissues.
It is currently unknown whether any ACEi is superior to any other in treating ankle oedema, but any ACEi initiated should be titrated according to blood pressure.
One randomised controlled trial found a lower prevalence of oedema in the group randomised to amlodipine in combination with ramipril (7.6%) compared to the group taking amlodipine alone (18.7%, P=0.011).
A systematic review found that a combination of a calcium channel blocker along with an angiotensin system blocker combination led to 38% fewer incidences of peripheral oedema than with a calcium channel blocker alone. This review was limited to Medline and Cochrane databases only and did not differentiate between ACEi and angiotensin II receptor blockers (ARB).
Angiotensin II Receptor Blockers (ARB)
The mechanisms by which ARBs reduce incidence of CCB-induced ankle oedema remains unknown, but are likely to be similar to that involved when an ACEi is added to CCB therapy.
One open-label, blinded end point study found a significant reduction in the incidence of markers of ankle oedema in the group treated with valsartan in addition to amlodipine versus amlodipine alone, along with significantly reduced blood pressure. This suggests that an ARB may be an effective alternative for treatment of oedema in patients unable to tolerate an ACEi.
A more recent study by the same authors compared valsartan and olmesartan effectiveness at reducing ankle oedema caused by amlodipine. Both ARBs reduced foot volume, but valsartan reduced oedema significantly more than olmesartan.
Nitrates, due to their venodilating action, may offer some useful effects in treating CCB-induced ankle oedema, but their use is limited by the practical considerations of having a stop-start regimen so tolerance does not develop.
Diuretics appear to have little effect on CCB-induced oedema, even where there is large natriuresis and a subsequent decrease in plasma volume.
This applies to both thiazide and loop diuretics, and is due to the fact that diuretics act by reducing water retention only. Diuretics do not affect vasodilatory-induced fluid pooling.
Discontinuation of CCB
If other treatment options fail, discontinuing the CCB and switching to an antihypertensive from another class of medicines may be required.
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