ONTARGET results

Nothing has helped advance Dr. Onuigbo’s cause as much as the ONTARGET findings (N Eng J Med. 2008:358:1547-1559).The study showed that a combination of telmisartan and ramipril reduces proteinuria to a greater extent than monotherapy, but overall, the combination worsens major renal outcomes.

In fact, the authors of the ONTARGET report, in a post hoc analysis, concluded that proteinuria reduction by itself cannot be taken as a definitive marker of improved renal function and that the benefits of any treatment, including combination RAAS blockade on major renal outcomes, remain to be demonstrated (Lancet. 2008:372(9638):547-553). Dr. Onuigbo felt vindicated.

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“The ONTARGET investigators were hoping to prove that combining the ACE inhibitor with the ARB would fix everything—reduce hypertension and protect the kidneys even more—because all along there has been this push that angiotensin II is the bad guy,” Dr. Onuigbo said.

“Any ACE that escaped the ACE inhibitor would be double-blocked with the ACE inhibitor and the ARB, and you would be done. I thought that was ridiculous, but again, we had to wait for the results. Now I can say it: Surprise, surprise. The combination group had more renal failure, more patients left on dialysis, more deaths, and more hyperkalemia, despite lower blood pressure and despite much greater reductions in urinary protein.”

Dr. Onuigbo emphasized that angiotensin II is key to sodium reabsorption, potassium secretion, homeostasis, BP control, and many other aspects of renal function. More recently, angiotenisn II has been implicated in genetic pathways involved in sustaining renal repair mechanisms following renal injury (Kidney Int. 2004:66:2181-2192; Am J Physiol Renal Physiol. 2007:292:F946-F955).

“It doesn’t make any sense at all physiologically that you can shut down such a critically important molecule in everybody and expect to get very good results, irrespective of the presence or absence of proteinuria,” Dr. Onuigbo added emphatically.

After the publication of ONTARGET, Dr. Onuigbo went back and reviewed some of the big trials, such as the substudy of the Heart Outcomes Prevention Evaluation Study that looked at microalbuminuria, cardiovascular, and renal outcomes (MICRO-HOPE) and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. He noticed that the P values rendered findings statistically significant but perhaps not clinically significant (QJM. 2009:102:155-167). He also noticed that many patients had dropped out of these studies.

“Drug discontinuation rates were upward of 20%-50% in those large trials,” he said. “If half those patients stopped taking the drug, how could you begin to relate outcomes with drug treatment?” The apparent lack of reduction in progression to end-stage renal disease (ESRD) and in mortality rates among ACE inhibitor and ARB users also troubles Dr. Onuigbo.

“If you look at the data in all those big trials that showed the ARB was better in protecting the kidneys and in preventing end-stage renal disease on dialysis, you would think that after three, four, or five years, you’d see some benefit in mortality. But in some cases, more patients in fact died in the ACE inhibitor/ARB treatment arm.”(QJM. 2009:102:155-167). Dr. Onuigbo does not blame the ARB for these deaths, but the findings suggest that “even if there was renal protection, it wasn’t big. The risk-benefit ratio may be good, but it’s clearly not huge.”

Dr. Onuigbo also pointed out what he considers a flaw in these studies: the use of composite albeit plausibly unrelated end points such as a combination of progression to ESRD, proteinuria reduction, and creatinine change. “Instead of looking at ESRD here vs. ESRD there, [investigators] would take ESRD, proteinuria reduction, and creatinine change together to make the results look good. Using these composite end points may make the picture murky” (QJM. 2009:102:155-167).

Angiotensin blockade use broadens

Angiotensin blockade for renoprotection came into broad use more than 15 years ago, after researchers finished the first major trial to show that ACE inhibitors protected the kidneys in people with type 1 diabetes (N Engl J Med. 1993;329:1456-1462).

“One might expect that by now we’d have seen a positive impact on national rates of ESRD thanks to these agents, but they haven’t seemed to make much of a dent,” Dr. Onuigbo said. In fact, he said, evidence suggests an upswing in ESRD cases in the United States after 1993, leading other researchers to speculate, many years ago, that ACE inhibitor use may have contributed to this trend (Kidney Int. 2005;67:1684-1691).

Also, in a population-based historical cohort analysis of 6,102 Canadian diabetic patients, Suissa et al. showed an increased ESRD rate ratio of 4.2 after three years or longer, of ACE inhibition, compared to diuretics, beta blockers and calcium channel blockers (Kidney Int.2006:69:913-919).

Despite Dr. Onuigbo’s view that some patients might be harmed by ACE inhibitors and ARBs, he said he still believes these agents are useful, good for BP control, and possibly renoprotective. “I don’t have anything against those drugs. I use them all the time for my patients,” Dr. Onuigbo said.

In fact, Dr. Onuigbo agrees with the current guideline that advises clinicians to follow kidney function during the initial several weeks of angiotensin blockade therapy and to stop treatment if serum creatinine levels jump by more than 30%.

The problem with this guideline, he said, is that it ends there, and does not address the management of any subsequent unexplained increases in serum creatinine that may occur in these patients, possibly years after drug initiation and on the same doses of these drugs.

Nobody has considered stopping ACE inhibitors and ARBs when patients experience later worsening renal failure and there were no other factors to explain it. “In my experience, a good number of these patients absolutely get better, following drug discontinuation,” Dr. Onuigbo said. His bottom line: Do not continue using the drugs based on the assumption that they have to be helping. “The entirety of the evidence for the renal protection provided by these agents is soft and not very strong,” he cautioned.

Another piece of advice that Dr. Onuigbo promotes, from results of his findings, is to discontinue temporarily the use of ACE inhibitors and ARBs before certain procedures.

“If my patients are going to have bypass surgery on Friday, I stop the drugs on [the previous] Monday, Tuesday, or Wednesday because major cardiovascular procedures are a big factor in kidney function loss. I believe that if you stop the drugs before the operation and resume them after, patients will do better.”

Here, at least, Dr. Onuigbo is not alone. In a five-year retrospective study of 1,358 adult patients who underwent cardiac surgery, preoperative use of ACE inhibitors and ARBs was associated with a 27.6% higher risk for acute kidney injury after cardiovascular surgery (Clin J Am Soc Nephrol. 2008;3:1266-1273).

Researchers concluded that stopping ACE inhibitors or ARBs before cardiac surgery may reduce the risk of such injury. In another similar report, Canadian researchers demonstrated improved renal outcomes in CKD patients undergoing cardiac catheterization, following the temporary discontinuation of RAAS blockade, when compared with historical controls (Clin Exp Nephrol. 2007:11:209-213).

But another study does not support Dr. Onuigbo’s view. Jordan Rosenstock, MD, a nephrologist at Lenox Hill Hospital in New York City, and colleagues randomized 220 patients with stage 3 or stage 4 CKD to continuation or discontinuation of ACE inhibitor or ARB therapy. These two groups were compared with a third group of stage 3 or stage 4 CKD patients who had not been taking these drugs.

The researchers found no significant difference in the incidence of contrast-induced nephropathy among the three groups and no significant difference among the groups in mean serum creatinine or eGFR values at baseline and post-contrast administration (Int Urol Nephrol. 2008;40:749-755).

In an interview with Renal & Urology News, Dr. Rosenstock stated, “I do believe that in stable patients with moderate kidney disease, there are significantly more important measures to focus on—such as making sure the patient is adequately hydrated—than holding ACE inhibitors or ARBs. In fact, if that is routinely done, we might run into more problems of uncontrolled hypertension during the procedure.”

Furthermore, Dr. Rosenstock, who is also a Clinical Assistant Professor of Medicine at New York University School of Medicine in New York City, disagrees with Dr. Onuigbo’s characterization of the evidence for renal protection provided by ACE inhibitors or ARBs as “soft.”

“There have been multiple well-designed trials in the renal literature showing clear benefit in patients with proteinuric kidney disease,” Dr. Rosenstock countered. “It is an important point, however, that the preponderance of data is in patients specifically with proteinuria.”

He added that there are certainly patients who are not helped by these medicines and in fact may even be harmed by them.

Ultimately, Dr. Rosenstock said, good clinical judgment is what matters. “I certainly wouldn’t recommend giving [ACE inhibitors or ARBs] blindly to all patients with kidney disease or heart disease,” he said. “Most nephrologists have seen patients in their practice who were hypotensive and clearly overmedicated with ACE inhibitors or ARBs and benefited from having the medicines reduced or stopped.”

Dr. Onuigbo agrees with Dr. Rosenstock about the need for good clinical judgment. “As long as the drugs are doing what we expect them to do, we should continue to use them,” he commented. He added, however, that “the acknowledgement and knowledge of the potential for nephrotoxicity of ACE inhibitors and ARBs must be emphasized and be borne in mind by practicing physicians, especially in the older patient population.”

In a recent literature review, Dr. Onuigbo unearthed additional past reports of nephrotoxicity with RAAS blockade—analogous to LORFFAB—in the CHARM [Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity]-Alternative program (Lancet. 2003:362:772-776) and the ALLHAT [Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack] diabetic population (Arch Intern Med. 2005:165:936-946). Patients on ACE inhibitors or ARBs experienced more acute renal failure and ESRD than those receiving comparator drugs.

Furthermore, Dr. Onuigbo said, there is a growing list of reports implicating ACE inhibitors and ARBs with cases of iatrogenic renal failure in various clinical scenarios, such as following cardiothoracic surgery and parenteral contrast administration (Nephron Clin Pract. 2009:in press).

Finally, Dr. Onuigbo said he believes that more and more reports supporting his viewpoint will emerge. Since his last review paper was published, he has received several supportive letters from practicing and retired nephrologists, including emeritus professors from within and outside the United States.

He was recently invited by a major nephrology journal to submit a mini-review on this topic and has been invited by medical schools around the country to give grand round presentations on his findings.