Combined angiotensin inhibition raises hyperkalemia, acute kidney injury risks

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Finding marks end of dual RAAS blockade – for now

The VA Nephron-D study adds to existing evidence suggesting that dual renin-angiotensin-aldosterone system (RAAS) blockade does not decrease cardiovascular and renal morbidity, and actually carries increased risks, Dr. Dick de Zeeuw wrote in an editorial that accompanied the study by Fried, et al., in the New England Journal of Medicine.

"The effect of these ‘failed’ trials goes beyond the decision about whether we should use dual RAAS blockade in order to better protect our patients with diabetes. The results suggest that improvement in surrogate markers – lower blood pressure or less albuminuria – does not translate into risk reduction," he said (N. Engl. J. Med. 2013 Nov. 9 [doi:10.1056/NEJMe1312412]).

The findings make it clear that dual RAAS blockade for the treatment of patients with diabetes cannot currently be recommended, he said, adding that "we need to find ways to design trials that ultimately provide a better balance between efficacy and safety.

"An enrichment design, selecting patients with a defined albuminuria response without adverse events, is a first step and is currently being tested," he said.

While future studies will likely "measure and integrate multiple drug responses to predict the chance of obtaining positive hard outcomes," for now, dual RAAS blockade can only be resuscitated if it can be shown that renal and cardiovascular protection is possible in a defined group of patients in whom the desired effects (decreased blood pressure and/or albuminuria) can be achieved without increasing the risk of hyperkalemia and other side effects, he concluded.

Dr. de Zeeuw reported serving as an adviser or steering committee chair for AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, ChemoCentryx, Johnson & Johnson, and Novartis, all of which have paid fees to his institution.

Dr. de Zeeuw is with the department of clinical pharmacology, University of Groningen, and University Medical Center Groningen, in the Netherlands.



ATLANTA – The combined use of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker was associated with an increased risk of hyperkalemia and acute kidney injury in patients with diabetic nephropathy in a randomized, controlled trial that was halted early because of these safety concerns.

"The risk-benefit ratio does not support the use of these medications – they’re not safe," noted Dr. Linda F. Fried, speaking at Kidney Week 2013.

The VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes) study involved 1,448 patients with type 2 diabetes and moderate diabetic nephropathy who were treated for at least 30 days with 100 mg daily of the angiotensin-receptor blocker (ARB) losartan, as is standard practice in patients with diabetes. The patients were randomized to also receive 10-40 mg daily of the angiotensin-converting enzyme (ACE) inhibitor lisinopril or placebo.

At a median follow-up of 2.2 years as of the time the study was stopped, 152 patients in the combination-therapy group and 132 in the placebo group (21% vs. 18.2%) experienced the composite primary endpoint of first occurrence of a predefined change in the estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), or death (hazard ratio with combination therapy, 0.88). The difference between the groups was not statistically significant, said Dr. Fried, professor of medicine, epidemiology, and clinical and translational science at the University of Pittsburgh and chief of peritoneal dialysis at Veterans Affairs Pittsburgh Healthcare System.

Despite an early trend toward benefit, this trend diminished over time so that no significant difference was seen between the groups in the secondary renal end point of a first occurrence of a decline in the eGFR or ESRD (hazard ratio, 0.78). Also, no difference was seen between the groups with respect to the safety outcome of mortality (HR for death, 1.04). The rate of cardiovascular events in the groups was also similar.

However, there was a greater than twofold increase in the risk of hyperkalemia in the combination therapy group, compared with the placebo group (6.3 vs. 2.6 events/100 person-years), and a nearly twofold increase in the risk of acute kidney injury in the combination therapy group (12.2 vs. 6.7 event/100 person-years), Dr. Fried said at the conference, which was sponsored by the American Society of Nephrology.

The findings were published concurrently in the New England Journal of Medicine (2013 Nov. 9 [doi10.1056/NEJMoa1303154]).

Patients in the study had type 2 diabetes, a urinary albumin-to-creatinine ratio of at least 300, and an eGFR of 30.0 to 89.9 mL/minute per 1.73 m2 or body-surface area. Change in eGFR as specified for the composite primary endpoint of the study was a decline of at least 30 mL/minute per 1.73 m2 in those with an initial eGFR of at least 60 mL/minute per 1.73 m2, or a decline of at least 50% if the initial eGFR was less than 60 mL/minute per 1.73 m2.

Treatment with medications that block angiotensin are known to slow loss of kidney function in individuals with diabetes and proteinuria. This is true for both ACE inhibitors and ARBs, which have different mechanisms of action, but the percentage of patients who progress to dialysis despite treatment with one of these medications remains high, Dr. Fried said.

"So we need more treatments. A question that comes up is, ‘Would more intensive blockade of angiotensin – using two (drugs) together – slow decline?’ ... The thought was that treatments that lowered proteinuria should lower progression. We did see the lower proteinuria but without the benefit on the endpoints," she said during a press briefing in advance of the presentation of the late-breaking abstract.

Instead, it became clear that the treatment was associated with significantly more hyperkalemia and kidney injury, she said, noting that significantly more patients in the combination therapy group experienced acute kidney injury requiring hospitalization, indicating the problem was not just one of "lab abnormalities."

In fact, for every 100 persons followed for 1 year, there were 17 more admissions to the hospital, Dr. Fried said, noting that "these were not small differences in safety outcomes."

"The risk-benefit ratio does not support the use of these medications – they’re not safe." she concluded.

The VA-Nephron-D study was supported by the cooperative studies program of the Department of Veterans Affairs Office of Research and Development. The Investigator-Initiated Studies Program of Merck provided the study drugs. Dr. Fried reported receiving support from Reata Pharmaceuticals as a site investigator for a study. Other studies authors reported receiving lecture or consulting fees from Merck, Sanofi-Aventis, Complex, and/or CytoPherx.

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