Medicines Q&As

Q&A 322.2

What are the reported incidences of ankle oedema with different calcium channel blockers?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: 13th May 2013

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 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 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 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 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 “membranophilic” (such as lercanidipine and lacidipine), may be associated with a lower incidence of ankle oedema 2.

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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 dose- proportional 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.

Reported Incidences: Drug Source Incidence of Ankle Oedema Notes Dihydropyridine CCBs Amlodipine Summary of Common >1/100 to <1/10 Product Characteristics (SPC)- Amlostin11 Andresdottir MB et 47% N=32 al, 2000 5 Lower limb volume measured by water displacement- may have included clinically insignificant increases in foot volume. Funded by drug manufacturers. Lombardo D et al 23% Subjective reporting 19945,12 Per Lund- 33.3% N= 44 Johansen 20037 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. Nifedipine SPC- Adalat13 Common >1/100 to <1/10 Oedema- not specified into what type Terry RW, 198214 7.7%- general population Review of 3081 patients with angina 10.3% in CHF subgroup pectoris. 8.2% in concomitant beta blocker therapy subgroup 11.6%- long term therapy subgroup. Blankfield RP, 1.7-32% Review of 7 papers 200510 MATH and EXACT 7.7% at 18 weeks and 8.1% at XL formulation of nifedipine trials8,15,16 20 weeks Felodipine SPC- Plendil17 Very Common >1/10 Peripheral oedema “As with other dihydropyridines dose dependent ankle swelling can occur in patients treated with felodipine, This results from precapillary vasodilation and is not related to generalised fluid

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retention. Experience from clinical trials has shown that 2% of patients interrupted treatment due to ankle swelling.” Saltiel E et al 4-30% Review 198818 Blankfield RP, 0-29.6% Review of 8 papers 200510 19 Lercanidipine SPC- Zanidip Uncommon- (>1/1000 <1/100) Peripheral oedema- not specified into what type Per Lund- 9.8% N=48 Johansen 20037 Post menopausal hypertensive patients. Isradipine SPC- Prescal20 Very common ( 1/10) Peripheral oedema- not specified into what type. STOP-2 trial21 25.5% Randomised, open masked-endpoint trial Blankfield RP, 7.7-13.9% Review of 2 trials 200510 Lacidipine SPC- Motens22 Oedema Common> 1/100, <1/10 Andresdottir MB et 20% N=30 al, 20005 Lower limb volume measured by water displacement- may have included clinically insignificant increases in foot volume. Funded by drug manufacturers. Blankfield RP, 6% Review 200510 Lindholm LH et al 4% Review (via Andresdottir) 19965,23 Subjective reporting Nimodipine SPC- Nimotop24 Not listed Non-dihydropyridine CCBs Diltiazem SPC-Angitil Very Common (>1/10) Peripheral oedema SR/XL25 Blankfield RP, 2.6-8.9% Review of 8 papers 200510 Verapamil SPC (Securon Ankle oedema mentioned but no SR)26 incidence given. White et al 200127 2.8% Review article- n= 1042 General oedema- not just ankle oedema Blankfield RP 0.7-13.5% Review of 5 papers 200510

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 amlodipine2,6. Diltiazem, a non-DHP agent, seems to be associated with the lowest incidence of ankle oedema8.

Limitations Reporting of ankle oedema may be subjective, and methods to detect oedema formation were

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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.

Quality Assurance

Prepared by Original Q&A written by: Vincent James Cassidy and Hayley Johnson, Regional Drug & Therapeutics Centre, Newcastle upon Tyne Update by: Vincent Cassidy

Date Prepared 13th May 2013

Checked by Original checked by Sahima Rahman, Regional Drug & Therapeutics Centre, Newcastle upon Tyne Update checked by: Hayley Johnson

Date of check Original: 29th June 2011 Update: 11th July 2013

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

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.

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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]. 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; 1003- 1010. 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. 11 Summary of Product Characteristics- Amlostin (amlodipine). Discovery Pharmaceuticals. Accessed via http://www.medicines.org.uk/EMC/medicine/15144/SPC/Amlostin+10mg/ on 13th May 2013 [last updated on the eMC: 29/02/2012] 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/SPC/Adalat/ on 13th May 2013 [last updated on the eMC: 01/07/2010] 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/SPC/Plendil+2.5mg%2c+Plendil+5mg+and+Plendil+ 10mg/ on 13th May 2011 [last updated on the eMC: 16/08/2012] 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 Pharmacetucicals. Accessed via http://www.medicines.org.uk/EMC/medicine/17624/SPC/Zanidip+10+mg+tablets/ on 13th May 2011 [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 13th May 2013 [Last updated on the eMC: 20/12/2017] 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/ accessed on 13th May 2013 [Last updated on the eMC: 27/11/2012] 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.

Available through NICE Evidence Search at www.evidence.nhs.uk 5

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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 13th May 2013 [Last updated on the eMC: 18/10/2012] 25 Summary of Product Characteristics: Angitil 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 13th May 2013 [last updated on the eMC: 08/02/2011] 26 Summary of Product Characteristics: Securon SR. Abbott Laboratories. Accessed via http://www.medicines.org.uk/EMC/medicine/20808/SPC/Securon+SR/ on 13th May 2013 [Last updated on the eMC: 19/03/2013] 27 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

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