Nancy A. Melville

November 19, 2013

ATLANTA — The combination of an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin-receptor blocker (ARB) increases the risk for serious adverse effects in patients with diabetic nephropathy, according to NEPHRON-D, a large multicenter study that was stopped early.

The research, known as the Veterans Affairs Nephropathy in Diabetes study, was presented here at Kidney Week 2013 and was also published in the New England Journal of Medicine (2013;369:1892-1903).

Investigators report that hyperkalemia was significantly higher with combination therapy than with monotherapy (6.3 vs 2.6 events per 100 person-years; < .001), as was acute kidney injury (12.2 vs 6.7 events per 100 person-years; < .001).

"The significant increase in risk overshadowed a nonsignificant trend toward a benefit with respect to the primary and secondary end points," said lead investigator Linda Fried, MD, from the VA Pittsburgh Healthcare System.

The study involved 1448 veterans with type 2 diabetes, albuminuria, and stage 2 or 3 chronic kidney disease. The average age of the cohort was 64 years. Investigators randomized patients to receive either the ACE inhibitor lisinopril 10 to 40 mg/day or placebo. All patients also received the ARB losartan 100 mg/day.

At a median follow-up of 2.2 years, there was no significant difference in the study's primary end point of renal disease progression or death between the monotherapy and combination therapy groups (152 vs 132; P = .30). There was also no difference in cardiovascular events.

The study's data monitoring committee recommended the study be stopped in October 2012 because of an unfavorable risk-benefit ratio.

Two previous studies — the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) and the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) — showed no renal or cardiovascular benefits from combination ACE inhibitor and ARB therapy, and significant adverse events.

However, ONTARGET involved patients with an increased risk for cardiovascular disease but predominantly normal albumin excretion levels, and ALTITUDE involved patients with kidney disease and diabetes who were not necessarily proteinuric.

Safety Signals ONTARGET, ALTITUDE

"Our hypothesis was that in individuals with type 2 diabetes and overt proteinuria, the combination of ARBs and ACE inhibitors would slow the progression of kidney disease to a greater extent than monotherapy with an ARB," Dr. Fried explained.

"But overall, the risk-benefit ratio does not support the use of combination therapy in patients with diabetes and proteinuria," she added.

After her presentation, Dr. Fried was asked by a member of the audience whether these results represent the "death knell" for combination therapy or whether they are just a cautionary note about a more aggressive approach.

"If it wasn't for ONTARGET and ALTITUDE, we could redesign the study to see if closer attention to certain safety outcomes might change this," she noted. "But we have to recognize that we now have 3 studies that are negative and that really do show a safety signal."

In an editorial accompanying the published study, Dick de Zeeuw, MD, notes that the hypothesis that combination therapy would be more effective than monotherapy arose from the fact that neither ACE inhibitors nor ARBs alone fully block the renin-angiotensin-aldosterone system (RAAS).

 
We have to recognize that we now have 3 studies that are negative and that really do show a safety signal.
 

"Indeed, further decreases in blood pressure and albuminuria have been observed with different combinations of dual RAAS blockade using ACE inhibitors, ARBs, mineralocorticoid-receptor blockers, and direct renin inhibition," notes Dr. de Zeeuw, from the University Medical Centre in Groningen, the Netherlands.

"Such results have prompted many clinicians to use dual RAAS blockade," he points out. "However, when approved or off-label drug use is guided by changes in surrogate markers without proof from hard-outcome trials, problems may ensue."

"For now, dual RAAS blockade can be resuscitated only if we can show renal and cardiovascular protection in a defined group of patients in whom the desired decreases in blood pressure, albuminuria, or both are achieved without major increases in potassium levels or other side effects," notes Dr. de Zeeuw.

Jorge Cerda, MD, from the Albany Medical College and Capital District Renal Physicians in New York, said he agrees that this study offers a relatively conclusive response to the question of risks and benefits with combination therapy.

"This is very definitive. It answers the question clearly, showing that the combination doesn't help matters, and it is a risk," he told Medscape Medical News. "This was a well-designed and well-powered study that offers important and useful findings."

However, Dr. Cerda takes issue with the conventional failed or negative labels used in the study, and suggested that such connotations miss the importance of the findings. "I don't know if I would even call it a negative study," he explained.

"In fact, you could say it's positive in the sense that a lot of patients may be spared the risk that they could have faced had they been treated with these drugs together," he noted.

The point is an important one, considering that positive studies are usually favored in medical journals, he said. "There is usually a tremendous bias by important journals in favor of positive studies, while negative studies are under-reported," Dr. Cerda said.

"That is something we need to fix; positive and negative studies should be reported equally. In this case, the fact is that this study will change the way we practice," he noted.

This study was supported by the cooperative studies program of the Department of Veterans Affairs Office of Research and Development. Merck's investigator-initiated studies program provided the study drugs. Dr. Fried reports support from Reata Pharmaceuticals as a site investigator for a study. Some of Dr. Fried's coauthors report financial relationships with Merck, sanofi-aventis, Complexa, and CytoPherx. Dr. de Zeeuw reports financial relationships with AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, Chemocentryx, Johnson & Johnson, Novartis, Reata, and Takeda. Dr. Cerda has disclosed no relevant financial relationships.

Kidney Week 2013: the American Society of Nephrology. Late breaker abstract. Presented November 9, 2013.

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