Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin–angiotensin system

Journal of Human Hypertension volume 23, pages 503–511 (2009)Cite this article

Abstract

This review is aimed at examining calcium channel blocker (CCB)-related oedema and how this can be attenuated through the use of agents that inhibit the renin–angiotensin system. CCBs are effective antihypertensive agents, but their propensity for causing oedema may reduce compliance. A review of the literature has indicated that the absolute incidence of this side effect is difficult to determine because reported rates vary widely, a factor that may stem from differences in the surveillance technique (active vs passive). In a recent trial incorporating active surveillance, 25% of patients who received amlodipine 10 mg per day experienced oedema. CCB-induced oedema is caused by increased capillary hydrostatic pressure that results from preferential dilation of pre-capillary vessels. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) cause post-capillary dilation and normalize hydrostatic pressure, and are thus ideally suited for prevention/reversal of CCB-induced oedema. The efficacy of this strategy was proven using both subjective and objective techniques. ARB/CCB and ACEI/CCB combination therapy is also more effective than CCB monotherapy in controlling blood pressure. These combinations represent an important advance in the management of hypertension.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42 (6): 1206–1252.

    Article  CAS  PubMed  Google Scholar 

  2. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G et al. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007; 28 (12): 1462–1536.

    PubMed  Google Scholar 

  3. National Collaborating Centre for Chronic Conditions. Hypertension: Management in Adults in Primary Care: Pharmacological Update 2006. Royal College of Physicians: London.

  4. Allemann Y, Fraile B, Lambert M, Barbier M, Ferber P, Izzo Jr JL . Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study. J Clin Hypertens (Greenwich) 2008; 10 (3): 185–194.

    Article  CAS  Google Scholar 

  5. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R . The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther 2008; 30 (4): 587–604.

    Article  CAS  PubMed  Google Scholar 

  6. Philipp T, Smith TR, Glazer R, Wernsing M, Yen J, Jin J et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. Clin Ther 2007; 29 (4): 563–580.

    Article  CAS  PubMed  Google Scholar 

  7. Poldermans D, Glazes R, Kargiannis S, Wernsing M, Kaczor J, Chiang YT et al. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension. Clin Ther 2007; 29 (2): 279–289.

    Article  CAS  PubMed  Google Scholar 

  8. Smith TR, Philipp T, Vaisse B, Bakris GL, Wernsing M, Yen J et al. Amlodipine and valsartan combined and as monotherapy in stage 2, elderly, and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies. J Clin Hypertens (Greenwich) 2007; 9 (5): 355–364.

    Article  CAS  Google Scholar 

  9. Malacco E, Vari N, Capuano V, Spagnuolo V, Borgnino C, Palatini P . A randomized, double-blind, active-controlled, parallel-group comparison of valsartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: the Val-Syst study. Clin Ther 2003; 25 (11): 2765–2780.

    Article  CAS  PubMed  Google Scholar 

  10. Messerli FH . Vasodilatory edema: a common side effect of antihypertensive therapy. Am J Hypertens 2001; 14 (9 Pt 1): 978–979.

    Article  CAS  PubMed  Google Scholar 

  11. Messerli FH . Vasodilatory edema: a common side effect of antihypertensive therapy. Curr Cardiol Rep 2002; 4 (6): 479–482.

    Article  PubMed  Google Scholar 

  12. Sica DA . Calcium channel blocker-related periperal edema: can it be resolved? J Clin Hypertens (Greenwich) 2003; 5 (4): 291–294, 297.

    Article  Google Scholar 

  13. Aranda P, Tamargo J, Aranda FJ, Luque M, Lopez-Garcia-Franco A . Use and adverse reactions of antihypertensive drugs in Spain. Part I of the RAAE Study. Blood Press Suppl 1997; 1: 11–16.

    CAS  PubMed  Google Scholar 

  14. Weir MR . Incidence of pedal edema formation with dihydropyridine calcium channel blockers: issues and practical significance. J Clin Hypertens (Greenwich) 2003; 5 (5): 330–335.

    Article  CAS  Google Scholar 

  15. Fogari R, Malamani G, Zoppi A, Mugellini A, Rinaldi A, Fogari E et al. Effect on the development of ankle edema of adding delapril to manidipine in patients with mild to moderate essential hypertension: a three-way crossover study. Clin Ther 2007; 29 (3): 413–418.

    Article  CAS  PubMed  Google Scholar 

  16. Fogari R, Malamani GD, Zoppi A, Mugellini A, Rinaldi A, Vanasia A et al. Effect of benazepril addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens 2003; 17 (3): 207–212.

    Article  CAS  PubMed  Google Scholar 

  17. Fogari R, Zoppi A, Derosa G, Mugellini A, Lazzari P, Rinaldi A et al. Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens 2007; 21 (3): 220–224.

    Article  CAS  PubMed  Google Scholar 

  18. Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC . Combined enalapril and felodipine extended release (ER) for systemic hypertension. Enalapril–Felodipine ER Factorial Study Group. Am J Cardiol 1997; 79 (4): 431–435.

    Article  CAS  PubMed  Google Scholar 

  19. Guazzi MD, De Cesare N, Galli C, Salvioni A, Tramontana C, Tamborini G et al. Calcium-channel blockade with nifedipine and angiotensin converting-enzyme inhibition with captopril in the therapy of patients with severe primary hypertension. Circulation 1984; 70 (2): 279–284.

    Article  CAS  PubMed  Google Scholar 

  20. Kuschnir E, Acuna E, Sevilla D, Vasquez J, Bendersky M, Resk J et al. Treatment of patients with essential hypertension: amlodipine 5 mg/benazepril 20 mg compared with amlodipine 5 mg, benazepril 20 mg, and placebo. Clin Ther 1996; 18 (6): 1213–1224.

    Article  CAS  PubMed  Google Scholar 

  21. Messerli FH, Oparil S, Feng Z . Comparison of efficacy and side effects of combination therapy of angiotensin-converting enzyme inhibitor (benazepril) with calcium antagonist (either nifedipine or amlodipine) versus high-dose calcium antagonist monotherapy for systemic hypertension. Am J Cardiol 2000; 86 (11): 1182–1187.

    Article  CAS  PubMed  Google Scholar 

  22. Messerli FH, Weir MR, Neutel JM . Combination therapy of amlodipine/benazepril versus monotherapy of amlodipine in a practice-based setting. Am J Hypertens 2002; 15 (6): 550–556.

    Article  CAS  PubMed  Google Scholar 

  23. Gustafsson D . Microvascular mechanisms involved in calcium antagonist edema formation. J Cardiovasc Pharmacol 1987; 10 (Suppl 1): S121–S131.

    Article  CAS  PubMed  Google Scholar 

  24. Gustafsson D, Grande PO, Borgstrom P, Lindberg L . Effects of calcium antagonists on myogenic and neurogenic control of resistance and capacitance vessels in cat skeletal muscle. J Cardiovasc Pharmacol 1988; 12 (4): 413–422.

    Article  CAS  PubMed  Google Scholar 

  25. Pedrinelli R, Dell'Omo G, Mariani M . Calcium channel blockers, postural vasoconstriction and dependent oedema in essential hypertension. J Hum Hypertens 2001; 15 (7): 455–461.

    Article  CAS  PubMed  Google Scholar 

  26. Lund-Johansen P, Stranden E, Helberg S, Wessel-Aas T, Risberg K, Ronnevik PK et al. Quantification of leg oedema in postmenopausal hypertensive patients treated with lercanidipine or amlodipine. J Hypertens 2003; 21 (5): 1003–1010.

    Article  CAS  PubMed  Google Scholar 

  27. Borghi C, Prandin MG, Dormi A, Ambrosioni E . Improved tolerability of the dihydropyridine calcium-channel antagonist lercanidipine: the lercanidipine challenge trial. Blood Press Suppl 2003; 1: 14–21.

    Article  PubMed  Google Scholar 

  28. Hermans L, Deblander A, De Keyser P, Scheys I, Lesaffre E, Westelinck KJ . At equipotent doses, isradipine is better tolerated than amlodipine in patients with mild-to-moderate hypertension: a double-blind, randomized, parallel-group study. Br J Clin Pharmacol 1994; 38 (4): 335–340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Leonetti G, Magnani B, Pessina AC, Rappelli A, Trimarco B, Zanchetti A . Tolerability of long-term treatment with lercanidipine versus amlodipine and lacidipine in elderly hypertensives. Am J Hypertens 2002; 15 (11): 932–940.

    Article  CAS  PubMed  Google Scholar 

  30. Zanchetti A, Omboni S, La Commare P, De Cesaris R, Palatini P . Efficacy, tolerability, and impact on quality of life of long-term treatment with manidipine or amlodipine in patients with essential hypertension. J Cardiovasc Pharmacol 2001; 38 (4): 642–650.

    Article  CAS  PubMed  Google Scholar 

  31. Barrios V, Escobar C, Navarro A, Barrios L, Navarro-Cid J, Calderon A . Lercanidipine is an effective and well tolerated antihypertensive drug regardless the cardiovascular risk profile: The LAURA study. Int J Clin Pract 2006; 60 (11): 1364–1370.

    Article  CAS  PubMed  Google Scholar 

  32. de Divitiis O, Fazio S, Petitto M, Maddalena G, Contaldo F, Mancini M . Obesity and cardiac function. Circulation 1981; 64 (3): 477–482.

    Article  CAS  PubMed  Google Scholar 

  33. Nakajima T, Fujioka S, Tokunaga K, Matsuzawa Y, Tarui S . Correlation of intraabdominal fat accumulation and left ventricular performance in obesity. Am J Cardiol 1989; 64 (5): 369–373.

    Article  CAS  PubMed  Google Scholar 

  34. Wollina U, Abdel-Naser MB, Mani R . A review of the microcirculation in skin in patients with chronic venous insufficiency: the problem and the evidence available for therapeutic options. Int J Low Extrem Wounds 2006; 5 (3): 169–180.

    Article  PubMed  Google Scholar 

  35. Iftikhar I, Ahmed M, Tarr S, Zyzanski SJ, Blankfield RP . Comparison of obstructive sleep apnea patients with and without leg edema. Sleep Med 2008; 9 (8): 890–893.

    Article  PubMed  Google Scholar 

  36. Blankfield RP . Obstructive sleep apnea associated with leg edema. Am Fam Physician 2006; 73 (4): 589; author reply 589.

    PubMed  Google Scholar 

  37. Fogari R, Malamani GD, Zoppi A, Preti P, Vanasia A, Fogari E et al. Comparative effect of lercanidipine and nifedipine gastrointestinal therapeutic system on ankle volume and subcutaneous interstitial pressure in hypertensive patients: a double-blind, randomized, parallel-group study. Curr Ther Res 2000; 61 (21): 850–862.

    Article  CAS  Google Scholar 

  38. Levick JR, Michel CC . The effects of position and skin temperature on the capillary pressures in the fingers and toes. J Physiol 1978; 274: 97–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Salmasi AM, Belcaro G, Nicolaides AN . Impaired venoarteriolar reflex as a possible cause for nifedipine-induced ankle oedema. Int J Cardiol 1991; 30 (3): 303–307.

    Article  CAS  PubMed  Google Scholar 

  40. Hilleman DE, Ryschon KL, Mohiuddin SM, Wurdeman RL . Fixed-dose combination vs monotherapy in hypertension: a meta-analysis evaluation. J Hum Hypertens 1999; 13 (7): 477–483.

    Article  CAS  PubMed  Google Scholar 

  41. Pedrinelli R, Dell'Omo G, Melillo E, Mariani M . Amlodipine, enalapril, and dependent leg edema in essential hypertension. Hypertension 2000; 35 (2): 621–625.

    Article  CAS  PubMed  Google Scholar 

  42. Weir MR, Rosenberger C, Fink JC . Pilot study to evaluate a water displacement technique to compare effects of diuretics and ACE inhibitors to alleviate lower extremity edema due to dihydropyridine calcium antagonists. Am J Hypertens 2001; 14 (9 Pt 1): 963–968.

    Article  CAS  PubMed  Google Scholar 

  43. Fletcher AP . Spontaneous adverse drug reaction reporting vs event monitoring: a comparison. J R Soc Med 1991; 84 (6): 341–344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Greenko JA, Fine A, Kellachan L, Layton M . West Nile Virus Detection in New York City, 2000: Evaluation of Active and Passive Surveillance for Encephalitis and Aseptic Meningitis [Abstract] in 41st Annual Meeting of the Infectious Diseases Society of America, San Diego, CA, USA 2003.

  45. McMahon AW, Zinderman C, Ball R, Gupta G, Braun MM . Comparison of military and civilian reporting rates for smallpox vaccine adverse events. Pharmacoepidemiol Drug Saf 2007; 16 (6): 597–604.

    Article  CAS  PubMed  Google Scholar 

  46. Olsen SJ, Laosiritaworn Y, Siasiriwattana S, Chunsuttiwat S, Dowell SF . The incidence of pneumonia in rural Thailand. Int J Infect Dis 2006; 10 (6): 439–445.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Rosenthal S, Chen R . The reporting sensitivities of two passive surveillance systems for vaccine adverse events. Am J Public Health 1995; 85 (12): 1706–1709.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Schumm WR . Neurologic adverse events associated with smallpox vaccination in the United States--response and comment on reporting of headaches as adverse events after smallpox vaccination among military and civilian personnel. BMC Med 2006; 4: 27.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363 (9426): 2022–2031.

    Article  CAS  PubMed  Google Scholar 

  50. Julius S, Weber MA, Kjeldsen SE, McInnes GT, Zanchetti A, Brunner HR et al. The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy. Hypertension 2006; 48 (3): 385–391.

    Article  CAS  PubMed  Google Scholar 

  51. Kloner RA, Weinberger M, Pool JL, Chrysant SG, Prasad R, Harris SM et al. Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators. Am J Cardiol 2001; 87 (6): 727–731.

    Article  CAS  PubMed  Google Scholar 

  52. Jarernsiripornkul N, Krska J, Capps PA, Richards RM, Lee A . Patient reporting of potential adverse drug reactions: a methodological study. Br J Clin Pharmacol 2002; 53 (3): 318–325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bond WS, Hussar DA . Detection methods and strategies for improving medication compliance. Am J Hosp Pharm 1991; 48 (9): 1978–1988.

    CAS  PubMed  Google Scholar 

  54. Van Wijk BL, Klungel OH, Heerdink ER, de Boer A . Rate and determinants of 10-year persistence with antihypertensive drugs. J Hypertens 2005; 23 (11): 2101–2107.

    Article  CAS  PubMed  Google Scholar 

  55. Andrade SE, Walker AM, Gottlieb LK, Hollenberg NK, Testa MA, Saperia GM et al. Discontinuation of antihyperlipidemic drugs—do rates reported in clinical trials reflect rates in primary care settings? N Engl J Med 1995; 332 (17): 1125–1131.

    Article  CAS  PubMed  Google Scholar 

  56. Claxton AJ, Cramer J, Pierce C . A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001; 23 (8): 1296–1310.

    Article  CAS  PubMed  Google Scholar 

  57. Cohen JS . Adverse drug effects, compliance, and initial doses of antihypertensive drugs recommended by the Joint National Committee vs the Physicians' Desk Reference. Arch Intern Med 2001; 161 (6): 880–885.

    Article  CAS  PubMed  Google Scholar 

  58. Dusing R, Weisser B, Mengden T, Vetter H . Changes in antihypertensive therapy—the role of adverse effects and compliance. Blood Press 1998; 7 (5–6): 313–315.

    CAS  PubMed  Google Scholar 

  59. Karow A, Czekalla J, Dittmann RW, Schacht A, Wagner T, Lambert M et al. Association of subjective well-being, symptoms, and side effects with compliance after 12 months of treatment in schizophrenia. J Clin Psychiatry 2007; 68 (1): 75–80.

    Article  PubMed  Google Scholar 

  60. Tosteson AN, Grove MR, Hammond CS, Moncur MM, Ray GT, Hebert GM et al. Early discontinuation of treatment for osteoporosis. Am J Med 2003; 115 (3): 209–216.

    Article  PubMed  Google Scholar 

  61. Anderson RB, Hollenberg NK, Williams GH . Physical Symptoms Distress Index: a sensitive tool to evaluate the impact of pharmacological agents on quality of life. Arch Intern Med 1999; 159 (7): 693–700.

    Article  CAS  PubMed  Google Scholar 

  62. Law MR, Wald NJ, Morris JK, Jordan RE . Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. Br Med J 2003; 326 (7404): 1427.

    Article  CAS  Google Scholar 

  63. Kiortsis DN, Giral P, Bruckert E, Turpin G . Factors associated with low compliance with lipid-lowering drugs in hyperlipidemic patients. J Clin Pharm Ther 2000; 25 (6): 445–451.

    Article  CAS  PubMed  Google Scholar 

  64. Jamerson KA, Nwose O, Jean-Louis L, Schofield L, Purkayastha D, Baron M . Initial angiotensin-converting enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension. Am J Hypertens 2004; 17 (6): 495–501.

    Article  CAS  PubMed  Google Scholar 

  65. Neutel JM, Smith DH, Weber MA, Schofield L, Purkayastha D, Gatlin M . Efficacy of combination therapy for systolic blood pressure in patients with severe systolic hypertension: the Systolic Evaluation of Lotrel Efficacy and Comparative Therapies (SELECT) study. J Clin Hypertens (Greenwich) 2005; 7 (11): 641–646; quiz 647–8.

    Article  CAS  Google Scholar 

  66. Damasceno A, Santos A, Pestana M, Serrao P, Caupers P, Soares-da-Silva P et al. Acute hypotensive, natriuretic, and hormonal effects of nifedipine in salt-sensitive and salt-resistant black normotensive and hypertensive subjects. J Cardiovasc Pharmacol 1999; 34 (3): 346–353.

    Article  CAS  PubMed  Google Scholar 

  67. Menard J, Bellet M . Calcium antagonists-ACE inhibitors combination therapy: objectives and methodology of clinical development. J Cardiovasc Pharmacol 1993; 21 (Suppl 2): S49–S54.

    Article  PubMed  Google Scholar 

  68. Sica DA . Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs 2002; 62 (3): 443–462.

    Article  CAS  PubMed  Google Scholar 

  69. Bellet M, Sassano P, Guyenne T, Corvol P, Menard J . Converting-enzyme inhibition buffers the counter-regulatory response to acute administration of nicardipine. Br J Clin Pharmacol 1987; 24 (4): 465–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ohbayashi Y, Tsutamoto T, Sakaguchi T, Tanaka T, Kanamori T, Yokohama H et al. Effect of an angiotensin II type 1 receptor blocker, valsartan, on neurohumoral factors in patients with hypertension: comparison with a long-acting calcium channel antagonist, amlodipine. J Cardiovasc Pharmacol 2003; 42 (Suppl 1): S71–S74.

    Article  CAS  PubMed  Google Scholar 

  71. Asmar R . Targeting effective blood pressure control with angiotensin receptor blockers. Int J Clin Pract 2006; 60 (3): 315–320.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The author would like to thank Jackie Campbell from Wolters Kluwer Health, who provided medical writing support on behalf of Daiichi-Sankyo Europe.

Author information

Authors and Affiliations

  1. University of Barcelona, Barcelona, Spain

    A de la Sierra

Authors
  1. A de la Sierra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A de la Sierra.

Additional information

Conflict of interest

Dr de la Sierra has received consulting and/or lecture fees from Abbott, AstraZeneca, Bayer Schering Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Pfizer, Servier and Solvay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de la Sierra, A. Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin–angiotensin system. J Hum Hypertens 23, 503–511 (2009). https://doi.org/10.1038/jhh.2008.157

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2008.157

Keywords

This article is cited by

Search

Advanced search

Quick links