Download BSH`s formal response to MHRA - British Society for Heart Failure

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
Comments
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.