As a renal fellow, I have found myself reaching for
spironolactone more and more. It is very helpful when treating the patient with
resistant hypertension, but it continues to be under-utilized. Aside from the renal-centric
effects of aldosterone, there is evidence that mineralocorticoid receptor
activation is responsible for pathogenic remodeling (both structural and
electrical) after myocardial infarction. In fact, aldosterone is also produced by
the heart, and cardiac expression of the mineralocorticoid receptor is
increased in the setting of heart failure and MI. Perhaps aldosterone
antagonists can reverse the cardiac remodeling, predisposition to arrhythmia,
and risk of cardiovascular death we see in our kidney disease patients?Remember, patients with ESRD do not die from kidney failure per se, but most die from cardiovascular and cerebrovascular disease. We know that spironolactone reduces mortality and hospitalization due to heart failure in patients with reduced LVEF (RALES trial), but we don’t know if these effects carry over to the ESRD population. However, two recent papers caught my eye.
One was recently published
in JACC, where 309 patients with ESRD were randomized to spironolactone 25mg
once daily or a control group. The primary outcome was a composite of death or
hospitalization from cardiovascular and cerebrovascular events, and the
secondary outcome was death from any cause. At three years, the treatment group
had significantly fewer cardiovascular and cerebrovascular events: 9 patients
(5.7%) vs 19 (12.5%) in the control group (Adjusted HR 0.379, p = 0.016). There
were also fewer deaths: 10 (6.4%) with spironolactone vs 30 (19.7%) in control
group (Adjusted HR 0.335, p=0.003). Out of the 157 patients in the
spironolactone group who stopped the drug, 7 developed gynecomastia, 9 had breast
pain, and 3 patients had significant hyperkalemia (>6.5 meq/L). Of course,
this was a small RCT and not blinded or placebo controlled. If these effects
are true, this would yield a NNT of 14 to prevent one cardiovascular or
cerebrovascular event and a NNH of 52 to cause one episode of hyperkalemia.
A similar study published in JASN
randomized 158 patients on PD and already on ACE/ARB therapy to 25mg of
spironolactone or a control group. After
two years of follow up, the rate of change of LVMI was significantly lower at
6, 18, and 24 months in the spironolactone group. In a subgroup analysis of
males who started the trial with LVMI ≤ 50 g/m2, the control group had a
significant increase in LVMI over time while the spironolactone treated group
was unchanged. Likewise, in males who started with LVMI > 50 g/m2, those
treated with spironolactone had a significant reduction in LVMI over time
compared to the controls. In this trial, serious hyperkalemia (>6.0)
occurred infrequently: 2 in spironolactone group and 1 in control. Gynecomastia
was more frequent in the spironolactone group (14.1% vs 2.5%), but some of
these patients had their doses reduced or were switched to eplerenone.
So what does this all mean? It’s exciting to think that
mineralocorticoid antagonists may reduce LVH and cardiovascular events in our ESRD
population. A larger, placebo controlled trial is needed to confirm these
findings since these were small open-label trials. Fortunately this is underway
with the ALCHEMIST trial (NCT01848639), which plans to randomize 825
hemodialysis patients to either spironolactone or placebo. In the meantime, it
may be best to use spironolactone as an anti-hypertensive agent in a dialysis
patient who is low risk for hyperkalemia. For instance, PD patients tend to
have have low serum potassium thanks to high clearance. In the PD patients I’ve
seen with hypertension and hypokalemia, I have been backing off pure
anti-hypertensive agents (like hydralazine) and starting 25mg of
spironolactone. These trials suggest that this dose is safe to use in dialysis
patients and possibly has some effect in preventing LVH and improving long-term
cardiovascular outcomes.
Posted by John Roberts
Posted by John Roberts
Interesting post. The cardiologists have grown increasingly excited about using aldactone, and indeed its use has a place.
ReplyDeleteHowever, how do we approach our patients who are not yet on dialysis when faced with the question of ACE or ARB + aldactone? Should we be asking ACE or ARB vs aldactone?
There is interest in using spironolactone in CKD patients, however the risk of hyperkalemia is a real concern. I would only use spironolactone in a CKD patient if they also have CHD with low EF and normal serum potassium. I would be more wary to use it if they have progressing CKD or are nearing dialysis. The strongest predictors of hyperkalemia when adding spironolactone is a eGFR less than 45 or baseline potassium greater than 4.5 meq/L. More monitoring is required when you add this medicine in advanced CKD.
ReplyDeleteI wondered about the use of ARBs in anuric patients on HD, speculating that it will not cause hyperkalemia because there is no residual renal function. I learned that these decrease colonic K secretion which becomes a major route of excretion of K in these cases.
ReplyDeleteI wonder whether spironolactone will have the same effect.