Mrha drug Safety Update (Spironolactone) summary

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MRHA Drug Safety Update (Spironolactone) - summary

Reminder for healthcare professionals:

•Concomitant use of spironolactone with ACEi or ARB is not routinely recommended because of the risks of severe hyperkalaemia, particularly in patients with marked renal impairment

•Use the lowest effective doses of spironolactone and ACEi or ARB if coadministration is considered essential

•Regularly monitor serum potassium levels and renal function

•Interrupt or discontinue treatment in the event of hyperkalaemia

•Suspected adverse reactions should be reported to us on a Yellow Card


The statement that “Concomitant use of spironolactone with ACEi or ARB is not routinely recommended” is incorrect in relation to the treatment of heart failure and reduced left ventricular ejection fraction (HF-REF). We are concerned that not only will this Drug Safety Update confuse physicians and nurse practitioners, but may also lead to patients being denied life-saving treatment. This is because the addition of a mineralocorticoid receptor antagonist (MRA), such as spironolactone or eplerenone, to an ACE inhibitor or ARB is generally recommended in all contemporary guidelines in patients with heart failure. This recommendation is made because two randomised controlled trials (RALES1 as mentioned in the MHRA document and EMPHASIS-HF2 which was not mentioned) each showed that addition of a MRA to background therapy, including an ACE inhibitor and ARB, reduced mortality and hospitalisation substantially in patients with HF-REF. These findings are supported by a third trial (EPHESUS) in patients with a reduced ejection fraction and heart failure after acute myocardial infarction, which also showed a reduction in mortality following the addition of eplerenone to an ACE inhibitor.3 Indeed, because of these three positive trials, addition of a MRA has the strongest recommendation (Class I Level A) in current guidelines.4,5 The benefits observed in the trials mentioned were obtained with a low risk of hyperkalaemia and renal dysfunction. However, available guidelines do give clear recommendations about patient and laboratory monitoring in order to minimise the risks of these adverse effects and also advise in which patients a MRA is not recommended (eGFR <30 ml/min/1.73m2) or a potassium >5.0 mmol/l. The British Society for Heart Failure suggest that this is the advice which should be disseminated to practitioners, rather than the MHRA advising avoidance of evidence-based pharmacological therapy.

We also think that the mention of dual blockade therapy with ACEi and ARB in the Drug Safety Update adds additional confusion – this is not relevant to the title of the update, nor its primary message. If dual blockade with both an ACEi and ARB is mentioned, it should only be so to remind practitioners that triple RAAS blockade (i.e. use of all of an ACE-I, ARB and MRA) should never be used (as stated in guidelines4,5).

1: Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999; 341:709-17.

2: Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309-21.

3: Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011; 364: 11-21.

4: McMurray JJ, Adamopoulos S, Anker SD, et al ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Eur J Heart Fail. 2012; 14: 803-69.

5: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013; 128: 1810-52.
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