Summary
Metolazone is a potent thiazide-like diuretic. It is recommended in severe congestive heart failure (HF). We conducted a review of the existing literature and found that the available information on the use of metolazone in HF is based on studies containing less than 250 patients in total. Nevertheless, metolazone is widely used, often in combination with a loop diuretic. Absorption of metolazone seems to be reduced in HF. Metolazone produces a diuretic response despite a low glomerular filtration rate. A wide dose range of metolazone has been investigated (≤2.5 to 200 mg), leaving no clear dosing recommendation. However, in most studies a low starting dose (≤5 mg) was used.
We further report an observational study on 21 patients with refractory systolic HF from our specialized outpatient HF clinic. The aim was to evaluate the effects of metolazone in combination with a loop diuretic in contemporary HF patients. Results: We registered 42 episodes of treatment with metolazone. The maximal dose of metolazone was 5 mg. NYHA functional class improved. A significant reduction during treatment in weight, blood pressure, plasma-sodium and –potassium was seen whereas plasma-BUN and –creatinine increased significantly. Clinically important hypokalemia (<2.5 mM) or hyponatremia (<125 mM) were observed during 10% of the treatment episodes.
Conclusion: The literature review and the observational study support the use of low-dose metolazone (≤5 mg) on top of oral loop diuretics, as an effective and relatively safe treatment in contemporary outpatients with refractory HF.
Similar content being viewed by others
References
Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diuretic treatment in severe heart failure: A randomised controlled trial. Br Heart J 1994;71:146–150.
Sica DA, Gehr TW. Diuretic combinations in refractory oedema states: Pharmacokinetic-pharmacodynamic relationships. Clin Pharmacokinet 1996;30:229–249.
Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–1560.
Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: Executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005;26:1115–1140.
Faggiano P, Opasich C, Tavazzi L, et al. Prescription patterns of diuretics in chronic heart failure: A contemporary background as a clue to their role in treatment. J Card Fail 2003;9:210–218.
Komajda M, Follath F, Swedberg K, et al. The EuroHeart Failure Survey programme: A survey on the quality of care among patients with heart failure in Europe. Part 2: Treatment. Eur Heart J 2003;24:464–474.
Ramahi TM, Longo MD, Rohlfs K, Sheynberg N. Effect of heart failure program on cardiovascular drug utilization and dosage in patients with chronic heart failure. Clin Cardiol 2000;23:909–914.
Grosskopf I, Rabinovitz M, Rosenfeld JB. Combination of furosemide and metolazone in the treatment of severe congestive heart failure. Isr J Med Sci 1986;22:787–790.
Tilstone WJ, Dargie H, Dargie EN, Morgan HG, Kennedy AC. Pharmacokinetics of metolazone in normal subjects and in patients with cardiac or renal failure. Clin Pharmacol Ther 1974;16:322–329.
Hinsvark ON, Cohen AI. The study of metolazone, a new diuretic, in human body fluids using thin layer separation, liquid chromatographic measurements and14C-counting techniques. Fed Proc 1970;29:276 (Abstract).
Modi KN, Iberra L, Nodine JH. Human pharmacokinetic studies with14C-Zaroxolyn, a new type of diuretic agent. Fed Proc 1970;29:276 (Abstract).
Sica DA, Brater D, Centor R, Davis J, Fakhry I. Metolazone-probenecid interaction in man. Clin Res 1987;35:381A (Abstract).
Steinmuller ST, Puschett JB. Effects of metolazone in man: Comparison with chlorothiazide. Kidney Int 1972;1:169–181.
Suki WN, Dawoud F, Eknoyan G, Martinez-Maldonado M. Effects of metolazone on renal function in normal man. J Pharmacol Exp Ther 1972;180:6–12.
Herbinger W. Diuretika in der Therapie der chronischen Herzinsuffizienz. Wien Med Wochenschr 1982;132:457–464.
Asscher AW. Treatment of frusemide resistant oedema with metolazone. Clin Trials J 1974;4:134–139.
Gunstone RF, Wing AJ, Shani HG, Njemo D, Sabuka EM. Clinical experience with metolazone in fifty-two African patients: Synergy with frusemide. Postgrad Med J 1971;47:789–793.
Epstein M, Lepp BA, Hoffman DS, Levinson R. Potentiation of furosemide by metolazone in refractory edema. Curr Ther Res 1977;21:656–667.
Reichgott MJ, Ram CVS. Synergism between metolazone and loop-diuretics. Clin Res 1977;25:275A (Abstract).
Sigurd B, Olesen KH, Wennevold A. The supra-additive natriuretic effect addition of bendroflumethiazide and bumetanide in congestive heart failure. Permutation trial tests in patients in long-term treatment with bumetanide. Am Heart J 1975;89:163–170.
Marone C, Muggli F, Lahn W, Frey FJ. Pharmacokinetic and pharmacodynamic interaction between furosemide and metolazone in man. Eur J Clin Invest 1985;15:253–257.
Aravot DJ, Banner NR, Musumeci F, et al. Oral metolazone plus frusemide for home therapy in patients with refractory heart failure. Lancet 1989;1:727–728.
Allen JM, Hind CR, McMichael HB. Synergistic action of metolazone with “loop” diuretics. BMJ 1981;282:1873.
Broadley AJ, Marshall AJ. Self administration of metolzaone reduces readmissions with decompensated congestive cardiac failure. Heart 1999;82:397–398.
Ghose RR, Gupta SK. Synergistic action of metolazone with “loop” diuretics. BMJ 1981;282:1432–1433.
Kröger N, Szuba J, Buhl C, Pompecki R, Frenzel H. Metolazone for severe dilated cardiomyopathy refractory to conventional therapy. Lancet 1990;335:1031–1032.
Kröger N, Szuba J, Frenzel H. Metolazone in der Behandlung fortgeschrittener therapieresistenter dilatativer Kardiomyopathie. Med Klin 1991;86:305–308, 332.
Galatius S, Gustafsson F, Nielsen PH, Atar D, Hildebrandt PR. An integrated approach to diagnosis and therapeutic management of patients with systolic heart failure in the Copenhagen metropolitan area. Am Heart J 2002;144:E2.
Hattersley AT, Langley S, Thompson JR, Blackwood RA. Home intravenous diuretic therapy for patient with refractory heart failure. Lancet 1989;1:446.
Stevenson LW, Dracup KA, Tillisch JH. Efficacy of medical therapy tailored for severe congestive heart failure in patients transferred for urgent cardiac transplantation. Am J Cardiol 1989;63:461–464.
Black WD, Shiner PT, Roman J. Severe electrolyte disturbances associated with metolazone and furosemide. South Med J 1978;71:380–1, 385.
Keogh B, Carmody M, Malone D, O'Dwyer WF. Clinical and biochemical evaluation of a new diuretic agent (Metolazone). J Ir Med Assoc 1971;64:255–260.
Gelfand ML, Cortega A, Lieu K. The use of metolazone in the treatment of congestive heart failure. J Clin Pharmacol 1974;14:396–397.
Levey BA, Palmer RF. Biochemical and clinical effects of metolazone in congestive heart failure. Curr Ther Res Clin Exp 1975;18:641–651.
Sheth UK, Mehta JM, Paul T, Sumati N, Sanghvi B. Clinical experience with metolazone—a new diuretic—in cases of edema and ascites due to hepatic cirrhosis, congestive cardiac failure and malnutrition. J Postgrad Med 1977;23:147–155.
Bonser RS, Ghose RR. Demeclocycline therapy for resistant oedema in advanced cardiac failure. Postgrad Med J 1980;56:121–123.
Furrer J, Hess OM, Kuhlmann U, Satz N, Siegenthaler W. Furosemid und Metolazon: Eine hochwirksame Diuretikakombination. Schweiz Med Wochenschr 1980;110: 1825–1829.
Bamford JM. Synergistic action of metolazone with “loop” diuretics. BMJ 1981;283:618.
Arosio E, Pancera P, Apolloni E, Covi G, Lechi A. Valutazione clinica del metolazone nelle sindromi edemigene. Clin Ter 1984;111:435–442.
Friedland JS, Ledingham JGG. Oral metolazone plus frusemide for home therapy in patients with refractory heart failure. Lancet 1989;1:727–728.
Kirancumar, Loureiro PA, Correia JM. Metolazone in the treatment of refractory heart insufficiency. Experience of 10 cases. Rev Port Cardiol 1989;8:775–778 (Abstract).
Kiyingi A, Field MJ, Pawsey CC, Yiannikas J, Lawrence JR, Arter WJ. Metolazone in treatment of severe refractory congestive cardiac failure. Lancet 1990;335:29–31.
Author information
Authors and Affiliations
Corresponding author
Additional information
The work originates from Cardiology Dept. Frederiksberg University Hospital, Frederiksberg, Denmark. Development of the ‘Hjerter +’ database was supported by an unrestricted grant by Merck, Sharp and Dohme, Denmark.
Rights and permissions
About this article
Cite this article
Rosenberg, J., Gustafsson, F., Galatius, S. et al. Combination Therapy with Metolazone and Loop Diuretics in Outpatients with Refractory Heart Failure: An Observational Study and Review of the Literature. Cardiovasc Drugs Ther 19, 301–306 (2005). https://doi.org/10.1007/s10557-005-3350-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10557-005-3350-2