Wednesday, May 12, 2010

A great combination

Since the retraction of the COOPERATE trial by the Lancet late last year (following Regina Kunz's famous 'letter of concern'), combination RAAS blockade has suffered something of a fall from grace. This was dealt a second blow by the results of the ONTARGET trial, where combination treatment in diabetics with vascular disease was associated with an increased rate of AKI and adverse events, without additional benefit. However, it must be remembered that patients in that trial did not have proteinuria, and the study endpoint was a composite outcome of death from cardiovascular causes, not progression of renal disease. As nephrologists, we are commonly faced with the problem of patients with CKD and heavy proteinuria not controlled by an ACE or ARB alone, and whom we know are at high risk for progressive renal disease. Is there evidence for combination therapy in this context?

In the latest AJKD, this trial by Bianchi et al. makes for provocative reading, although I feel the results must be interpreted with caution. They randomized 128 patients with a clinical diagnosis of idiopathic chronic GN to either intensive therapy (ACE + ARB + spironolactone + high dose statin) or conventional therapy (ACE + low dose statin). The endpoints were change in GFR, proteinuria and adverse events at 3 years. The intensive arm experienced a far greater reduction in proteinuria and stable GFR over time compared to the conventional arm (who lost ~ 7ml/min over the study period) at the expense of more hyperkalemia and discontinued therapy.

I was surprised at how little hyperkalemia developed in the intensive arm (9 vs 3 events). I would have to admit to being pretty nervous of triple RAAS blockade for fear of this complication. That said, if patients can tolerate the combination, the outcomes based on this small study look promising.

Thanks to Dr. Rafael Santamaria for bringing this trial to my attention.


Joel Topf said...

Ponch and Jon FTW

Raf999 said...

Dear friends,

It´s my pleasure.

In my personal opinion, several important points should be remarked that could explain the low rate of adverse events.

Firstly, the selection criteria. Patients with previous cardiovascular events, chronic heart failure, GFR below 30 ml/min/1.73m2 or those treated with non-steroidal anti-inflammatory drugs were excluded. It´s well known that this is the profile of patients in risk to develop adverse events when renin-angiotensin system (RAS) is intensively blocked.

Secondly, GFR of included patients. The mean value of GFR was 63.5+/-1.4 ml/min/1.73m2, which seems to indicate that the patients were at an early stage of the disease. For an average 53 years old male patient, a GFR of 63 ml/min/1.73m2 corresponds to a serum creatinine of 1.26 mg/dl.

And lastly, drugs, doses and follow-up. The maximun dose of spironolactone by protocol was 50 mg/d, but at baseline only 3 patients received this dose, 50 patients (78%) were treated with 25 mg/d, and 19% received even lower doses (75-100 mg/week) . From other studies we learnt that the risk of hyperkalemia in spironolactone treated patients is dose dependent, but it should be noted that patients included in these studies usually have hypoperfused kidneys (such as in RALES study with patients with chronic heart failure). The patients were very closely monitored, checking regularly for renal function and potassium concentration, adjusting treatments according to these values. According to this line, in a recent paper by Wei et al in BMJ ( in a population based longitudinal analysis, the authors studied the incidence of hyperkalemia using spironolactone, and they conclude that "Careful monitoring of patients prescribed spironolactone seems to have been associated with no increase in risk of hyperkalaemia". On the other hand, in the intensive treatment group 81% of the patients were receiving other diuretics at baseline (25% and 56% were treated with hidroclortiazide and furosemide, respectively).

In conclusion, it´s a provocative paper that arises more questions than answers, but probably the secrets of the authors' success could be summarized in strong RAS blockade, mild CKD and good follow-up and care of the patients.

Best regards,

Rafael SantamarĂ­a.