Spironolactone and risk of upper gastrointestinal events: population based case-control study

EDITOR – The discovery of a dose-dependent association between
spironolactone and gastrointestinal bleeding by Verhamme et al must have
caused a stir in the world of internal medicine. This conclusion was
drawn from a population based case-control study which derived its data
between 1996 and 2003. Interestingly RALES1 was published in 1999,
establishing the central role of spironolactone in treatment of severe
heart failure.

According to Verhamme et al, spironolactone was associated with a 2.7
-fold increase in upper gastrointestinal events, the association being
strongest in patients taking the higher doses. In RALES, 12.5mg, 25mg and
up to 50mg of spironolactone was used and there were no statistical
difference in the incidence of gastrointestinal events between the
treatment arm and the placebo arm. Standard doses of spironolactone in
treatment of hypertension and ascites in cirrhosis are up to 400mg; the
authors should therefore clarify what they considered to be a ‘defined
daily dose’.

Diagnoses of heart failure in primary care are often incorrect,2 but
patients prescribed spironolactone are more likely to have had severe left
ventricular dysfunction confirmed by echocardiography, as it is only in
patients with confirmed severe systolic dysfunction and persistent
symptoms that spironolactone is indicated. Considering diuretic dose
alone is unlikely to exclude confounding for severity of heart failure,
therefore.

The situation echoes one in hypertension in the mid-1990’s, when the
use of dihydropyridine calcium antagonists in hypertension was reported to
be associated with increased mortality,3 and there were calls for use of
these drugs to be restricted.4 Subsequent randomised trial data have
proven the efficacy and safety of dihydropyridine treatment,5 which is
actually superior to older medication. It is important that an
unconfirmed theory generated by observational data should not prevent
patients benefiting from the major prognostic benefit of spironolactone in
severe heart failure.

1Pitt 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. Randomized aldactone evaluation study
investigators. N Engl J Med 1999; 341:709-17.

2Remes J, Miettinen H, Reunanen A, Pyorala K. Validity of clinical
diagnosis of heart failure in primary health care. Eur Heart J 1991;12:315
-21.

3Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase
in mortality in patients with coronary heart disease. Circulation
1995;92:1326-31.

4Furberg CD, Psaty BM. Calcium antagonists: not appropriate as first
line antihypertensive agents. Am J Hypertens 1996;9:122-5.

5Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M,
Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M,
O'Brien E, Ostergren J; ASCOT Investigators. Prevention of cardiovascular
events with an antihypertensive regimen of amlodipine adding perindopril
as required versus atenolol adding bendroflumethiazide as required, in the
Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm
(ASCOT-BPLA): a multicentre randomised controlled trial. Lancet
2005;366:895-906.

Competing interests:
None declared