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• OMP Jolobe
  Published on: 9 January 2022
• Re: Don't blame spironolactone yet: Look at prescriber and patient related factors first?
  C Berry
  Published on: 9 January 2022
• Don't blame spironolactone yet: Look at prescriber and patient related factors first?
  Robert J MacFadyen
  Published on: 9 January 2022

• Published on: 9 January 2022

  • OMP Jolobe, Geriatrician

  Dear Editor

  The occurrence of drug-related prerenal uraemia and, hence, hyperkalemia [1,2] is an entirely predictable outcome if the precaution is not taken to reduce the dose of loop diuretics when sprironolactone is added to existing angiotensin converting enzyme (ACE) inhibitor therapy. This given the fact that the coprescription of all three modalities (ie spironolactone, loop diuretics, and ACE inhibitors) can...

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  Dear Editor

  The occurrence of drug-related prerenal uraemia and, hence, hyperkalemia [1,2] is an entirely predictable outcome if the precaution is not taken to reduce the dose of loop diuretics when sprironolactone is added to existing angiotensin converting enzyme (ACE) inhibitor therapy. This given the fact that the coprescription of all three modalities (ie spironolactone, loop diuretics, and ACE inhibitors) can powerfully augment diuresis even to the extent of precipitating prerenal uraemia [3,4] as a consequence of the enhancement of natriuresis arising from the synergism between spironolactone and ACE inhibitors [5].

  O M P Jolobe

  References
  (1) Berry C, McMurray JJV. Serious adverse events experienced by patients with chronic heart failure taking spironolactone. Heart 2001;85:e8(April).

  (2) Schepkens H, Vanholder R, Billouw J-M, Lamiere N. Life-threatening hyperkalaemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone. An analysis of 25 cases. American Journal of Medicine 2001;110:438-441.

  (3) Ikram H, Lewis GRJ, Webster MWI, Richards AM, Nicholls MG, Crozier IG. Combined spironolactone and converting enzyme inhibitor therapy for refractory heart failure. Australian and New Zealand Journal of Medicine 1986;16:61-63.

  (4) Jolobe OMP. Efficacy of low-dose captopril in addition to furosemide and spironolactone in patients with decompensated liver disease during blunted diuresis (letter). Journal of Hepatology 1993;19:321-322.

  (5) Bauersachs J, Fraccarollo D, Ertl G, Gretz N, Wehling M, Christ M. Striking increase of natriuresis by low-dose spironolactone in congestive heart failure only in combination with ACE inhibitors. Mechanistic evidence to support RALES. Circulation 2000;102:2325-2328.

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  Conflict of Interest:
  None declared.

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• Published on: 9 January 2022

  Re: Don't blame spironolactone yet: Look at prescriber and patient related factors first?

  • C Berry, Cardiologist

  Dear Editor,

  We thank Dr. MacFadyen for his thoughtful comments on our report. We were trying to draw to readers' attention, our observations that severe renal dysfunction and hyperkalaemia can occur when spironolactone is added to conventional therapy (and other, non-heart failure, drugs) in "real" patients with heart failure, a phenomenon not described in the carefully selected RALES population. Interesting...

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  Dear Editor,

  We thank Dr. MacFadyen for his thoughtful comments on our report. We were trying to draw to readers' attention, our observations that severe renal dysfunction and hyperkalaemia can occur when spironolactone is added to conventional therapy (and other, non-heart failure, drugs) in "real" patients with heart failure, a phenomenon not described in the carefully selected RALES population. Interestingly, similar concerns were recently aired at the Scientific Sessions of the American Heart Association [1]. While augmentation of diuresis may be the simple explanation for our findings, it has been argued that low dose spironolactone does not induce a diuresis and acts in other ways [2]. We also wished to specifically report the occurrence of diarrhoea with spironolactone, a possible adverse event that we have now seen in several patients and one which has occurred with delayed spironolactone rechallenge in two. Consequently, we think this is a real rather than false association. We are surprised that Dr. MacFadyen is surprised by our rate of use of spironolactone. One of the most common reasons for admission to our Cardiology ward is severe, end- stage, chronic heart failure and treatment with low dose spironolactone is indicated in these patients. We are glad, however, that he agrees that very careful monitoring of renal function is mandatory in patients starting spironolactone for heart failure.

  Reference List

  (1) Bozkurt B, Geraci JM, Knowlton AA. Spironolactone use in heart failure: Spiraling out of control? Circulation 2000;102:2002.

  (2) Cody RJ, Pitt B, Perez A, Bettman R. The benefit of spironolactone in the RALES Trial is not primarily due to a diuretic effect. Journal of the American College of Cardiology 2000;35:212A-.

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  Conflict of Interest:
  None declared.

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• Published on: 9 January 2022

  Don't blame spironolactone yet: Look at prescriber and patient related factors first?

  • Robert J MacFadyen, Consultant Physician and Cardiologist

  Dear Editor,

  Berry and McMurray (Heart 2001;85:e8) report three of four cases of serious adverse events in association with spironolactone linked to the non-specific symptom of diarrhoea. As cited, Professor McMurray many years ago reported the renal adverse effects of "diarrhoea" induced volume depletion in conjunction with ACE inhibition as a simple case study. I may have misinterpreted the recent report but I...

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  Dear Editor,

  Berry and McMurray (Heart 2001;85:e8) report three of four cases of serious adverse events in association with spironolactone linked to the non-specific symptom of diarrhoea. As cited, Professor McMurray many years ago reported the renal adverse effects of "diarrhoea" induced volume depletion in conjunction with ACE inhibition as a simple case study. I may have misinterpreted the recent report but I believe that this earlier interpretation (and not the one described in the above article) remains the correct origin of "pathology" in this present case study series.

  The authors appear to imply that Spironolactone per se causes drug- induced diarrhoea. While it is reasonable to speculate on this on the basis of their few cases, it is not at all easy to deduce such causality in a small and heterogeneous population of patients with heart failure, particularly in the patients treated here with several diuretics. The reason that the BNF does not note diarrhoea (rather than non-specific "gastro intestinal disturbance") as a side effect of spironolactone treatment is because this is, as yet, is not an associated adverse event attributable to drug treatment rather than confounding by association. This can be checked with the Medicines Control Agency and the manufacturer of the proprietary brand (GD Searle). Perhaps specific population data can be derived to address this by use of large-scale prescription event monitoring systems[1] but it is important to note that this is not yet an accepted association nor do these case reports define it as such.

  There are many who regard the effect of spironolactone in end stage CHF as wholly related to "more effective" diuresis.[2] Yet sodium and volume depletion can be fraught with danger for the few patients who qualify for this additional treatment (i.e. those and only those who fulfil RALES end stage severity), as is well illustrated by Berry and McMurray's case reports. I believe the cases presented can all be individually related to volume depletion related to well-recognised drug interactions (NSAID) and or multiple diuretic treatments in combination with end stage cardiac and cardio renal pathology. This is a problem that we recently noted in the Journal[3] for others, who in contrast to Berry and McMurray, were keen to promote an aggressive and largely unmonitored combination diuretic treatment[4] previously shown to be a source of difficulty in controlled hospital studies far less community use.[5] Berry and McMurray are absolutely right to caution against the unbridled use of Spironolactone. In the same way surely 45% of their routine cardiology patient discharges do not fit the RALES criteria? How did that happen in their own Department?

  In summary the adverse events noted relate more generally to the detrimental impact of multiple diuretic treatments on the kidneys and critical electrolyte balance. They show clearly how lives can be lost almost entirely due to these issues of drug selection. The relationship of Spironolactone with drug induced intestinal dysfunction and therefore secondary rather than primary drug related sodium and fluid loss is an interesting one but one whose primary step is not proven nor explained here. More obviously the adverse events relate to diuretic induced fluid and electrolyte loss and are therefore an extension of predicted pharmacological effect rather than any new and undefined effect although this remains possible? The correct caution here is to select the appropriate patients for Spironolactone and not to think of it as a "cure all" at all stages of the heart failure syndrome, which it clearly is not. Careful supervision of renal function is required for all CHF patients but particularly those who require combination diuresis whether for defined diuretic resistance, because of the severity of disease (RALES patient group) or by default. Combination diuretic pharmacology is a very well- researched topic[6] not helped by unrestricted drug prescription which obviously even occurs in a specialist heart failure unit.

  Robert J. MacFadyen, Cardiac Unit (7th Floor), Highland Acute Hospitals NHS Trust, Old Perth Road, Inverness IV2 3UJ

  References
  (1) Evans JM, MacDonald TM. Record-linkage for pharmacovigilance in Scotland. Br J Clin Pharmacol 1999;47:105-10.

  (2) Bauersachs J, Fraccarollo D, Ertl G, Gretz N, Wehling M, Christ M. Striking increase of natriuresis by low dose Spironolactone in congestive heart failure only in combination with ACE inhibition: mechanistic evidence to support RALES. Circulation 2000;102:2325-8.

  (3) MacFadyen RJ, Struthers AD. Diuretic use and abuse in systolic cardiac failure: a recipe for renal impairment? Heart 2000;83:468.

  (4) Broadley AJM, Marshall AJ. Self-administration of Metolazone reduces readmissions with decompensated congestive cardiac failure. Heart 1999;82:397-8.

  (5) Channer KS, McLean KA, Lawson-Matthew P, Richardson M. Combination diuretic treatment in severe heart failure: a randomised controlled trial. Br Heart J 1994;71:146-50.

  (6) Brater DC. Resistance to loop diuretics. Why to happens and what to do about it. Drugs 1985;30:427-43.

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  Conflict of Interest:
  None declared.

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