Dual Angiotensin Blockade May Harm Kidneys

By Crystal Phend
HAMILTON, Ontario, 15 aug 2008-- The angiotensin receptor blocker telmisartan (Micardis) and the ACE inhibitor ramipril (Altace) are individually equivalent against proteinuria, but the combination may be renotoxic, researchers suggested. Composite renal outcomes were almost exactly the same between telmisartan and ramipril (13.4% versus 13.5%), but event rates rose with combination therapy (14.5%, P=0.037), reported Johannes F.E. Mann, M.D., of McMaster University here and Munich General Hospitals in Germany, and colleagues in the Aug. 16 issue of The Lancet. These findings from the ONTARGET trial mirror the noninferiority of the drugs for cardiovascular outcomes reported earlier this year at the American College of Cardiology meeting.
In that analysis, telmisartan showed no more than a 2% reduction in risk of cardiovascular events compared with ramipril. But dual blockade was less tolerable with 3.28 times more diarrhea than ramipril, 1.95 times more syncope, and 2.75 times more hypotension reported as reasons for permanent discontinuation.
Both drug classes have also been shown to reduce proteinuria, and small studies had suggested that the combination could be even better.
In an accompanying commentary, Pantelis A. Sarafidis, M.D., Ph.D., of the Aristotle University of Thessaloniki, Greece, and George L. Bakris, M.D., of the University of Chicago, cautioned that ONTARGET may not conclusively answer questions about combination therapy for renal function.
However, the findings support guidelines recommending use of renin-angiotensin blocking drugs to lower blood pressure and urinary protein in chronic kidney disease but clearly admonish against use of dual blockade in people at low risk of chronic kidney disease, they said.
"In choosing between the two, if tolerability is an issue, certainly the angiotensin receptor blocker would be preferred to the ACE inhibitor," Dr. Bakris said. But if cost is an issue, the ACE inhibitor may win out, he noted.
The Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) study was designed to measure renal outcomes in addition to the main cardiovascular analysis.
The study included 25,620 high-risk patients ages 55 or older who had cardiovascular disease (85%) or diabetes (38%) but no heart failure. Most patients in the trial (69%) also had hypertension.
The researchers randomly assigned patients to 10 mg of ramipril per day, 80 mg of telmisartan per day, or both.
After a median 56 months of therapy, telmisartan and ramipril were equivalent for the primary composite renal outcome of dialysis, doubling of serum creatinine, and death (13.4% versus 13.5%, hazard ratio 1.00, 95% confidence interval 0.92 to 1.09). The similarities spanned all patient subgroups.
However, renal events in the primary outcome measure were significantly increased with combination therapy (14.5%, HR 1.09, P=0.037).
No subgroup of patients appeared to get clear benefit from dual blockade, even those at the highest risk with overt diabetic nephropathy or low baseline kidney function.
Patients at low renal risk-those without hypertension or diabetes-tended to be at greater harm with combination versus single agent therapy.
As expected from prior studies, combination therapy slowed the progression of proteinuria. New onset of microalbuminuria or macroalbuminuria was similar between the ARB and ACE inhibitor (11.1% versus 11.77%, P=0.119) but less common with combination therapy (10.4%, P=0.003 versus ramipril).
However, the surrogate endpoints "unexpectedly showed contrasting effects," the researchers noted.
The composite of any dialysis or doubling of serum creatinine was similar with the angiotensin receptor blocker and ACE inhibitor (2.21% versus 2.03%, HR 1.09, 95% CI 0.89 to 1.34). Again, though these events were more frequent with combination therapy (2.49%, HR 1.24, P=0.038).
Loss of kidney function was most rapid in the dual blockade group with a decline of 6 mL per minute estimated glomerular filtration rate for 56 months.
Drs. Sarafidis and Bakris noted that this translated to a reduction of 1.29 mL per minute per year, which was only slightly above the normal range of loss from 0.6 to 1.1 mL per minute per year and would not be considered a major loss.
Hypotensive symptoms leading to drug discontinuation were more common with combination therapy and telmisartan than ramipril (406 and 229 patients versus 149).
Renal abnormalities as a reason for permanently stopping medication were most common with combination therapy as well (1.1% versus 0.7% with ramipril and 0.8% with telmisartan, P<0.0050 versus ramipril).
The researchers noted that although the study was not powered specifically for major renal outcomes, the number of renal events was at least as high as in other trials that were powered to show a difference in kidney function.
They concluded that "there is no evidence to support the use of combination therapy in any subgroup of patients included in ONTARGET beyond lowering of urinary albumin excretion."
However, Drs. Sarafidis and Bakris felt that "the interpretation that the group receiving a combination regimen (ramipril and telmisartan) to block the renin-angiotensin system group had more renal events istroubling."
They concluded that "a properly done prospective trial of patients with advanced proteinuric chronic kidney disease is still needed to answer definitively the question about the efficacy of combination therapy to block the renin-angiotensin system on progression of chronic kidney [disease]."
Dr. Mann and a number of co-authors reported receiving consulting and lecture fees and research grants from Boehringer Ingelheim and from other companies manufacturing angiotensin receptor blockers. One author was an employee of Boehringer Ingelheim.
Dr. Bakris reported being a scientific adviser to Boerhinger Ingelheim. Dr. Sarafidis reported no conflicts of interest.
Primary source: The LancetSource reference:Mann JFE, et al "Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial" Lancet 2008; 372: 547-53. Additional source: The LancetSource reference: Sarafidis PA, Bakris GL "Renin-angiotensin blockade and kidney disease" Lancet 2008; 372: 511-512.