The angiotensin receptor blocker (ARB) telmisartan offers no renal benefit in adults who have a high vascular risk—but do not have macroalbuminuria—and are intolerant to angiotensin-converting enzyme (ACE) inhibitors, according to data from TRANSCEND (Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease) published in the Annals of Internal Medicine (2009;151:1–10).
In the study, which compared telmisartan with placebo, no significant differences in the composite renal outcome were observed.
These results clarify the understanding of the effects of telmisartan in this patient population, said lead author Johannes F. E. Mann, MD, Professor of Medicine and Head of the Department of Nephrology, Hypertension, and Rheumatology at Schwabing General Hospital at Ludwig-Maximilians-University in Munich, Germany, in a phone interview.
Although large studies of patients with overt diabetic nephropathy have shown a reduced rate of dialysis and doubling of serum creatinine with ARB use, the impact of such agents on renal outcomes in other patient populations was not reliably known, Dr. Mann and colleagues wrote.
Renal effects were prespecified secondary outcomes of TRANSCEND, a cardiovascular study funded by Boehringer Ingelheim. In the cardiovascular analysis, telmisartan had no statistically significant effect on the primary cardiovascular outcome, but it did reduce the risk for the secondary composite outcome of cardiovascular death, myocardial infarction, and stroke to a moderate extent, with no effect on cardiovascular or total mortality.
The cardiovascular and renal results shed light on the factors that should be considered when deciding whether or not to use telmisartan in a patient with atherosclerosis, Dr. Mann noted.
“The main impact is the cardiovascular results, and it's not the kidney that you should have in mind.”
Primary Outcome Switch
Between November 2001 and May 2004, 5,926 ACE-intolerant patients age 55 and older from 630 centers in 40 countries were enrolled in the study. Patients had known cardiovascular disease or diabetes with end-organ damage, but they did not have macroalbuminuria—defined as a urinary albumin-creatinine ratio (UACR) greater than 33.9 mg/mmol—or heart failure.
After a three-to-four-week run-in phase, during which all participants received single-blind placebo for one week followed by 80 mg/day of telmisartan for two to three weeks, participants were randomly assigned to telmisartan 80 mg/day (2,954 patients) or placebo (2,972 patients). Follow-up occurred at six weeks, six months, and every six months thereafter for a mean of 56 months.
Originally, the primary composite outcome was defined as first occurrence of dialysis, renal transplantation, doubling of serum creatinine, or death, while the secondary renal outcome was a composite of dialysis or doubling of serum creatinine.
After completion of the analysis, though, it was discovered that the nonspecific outcome of death outnumbered the other components of the primary outcome fourfold, so the secondary outcome was made the composite outcome measure for the analysis.
The incidences of the composite outcome of dialysis or doubling of serum creatinine were similar in the telmisartan and placebo groups, occurring in 58 and 46 patients, respectively.
While both groups had similar numbers of dialysis cases, more patients treated with telmisartan had a doubling of serum creatinine (56 patients vs 36 in the placebo group).
Incident albuminuria showed less of a rise with telmisartan than with placebo: Among the 559 patients with microalbuminuria at baseline (286 in the telmisartan group and 273 in the placebo group), 28 patients (9.8%) in the telmisartan group and 49 (17.9%) in the placebo group progressed to macroalbuminuria. The risk for developing microalbuminuria and/ or macroalbuminuria during the trial was lower with telmisartan than with placebo.
Regarding changes in estimated glomerular filtration rate (eGFR), telmisartan led to a greater decrease (a mean decline of 3.2 mL/min/1.73 m2) than did placebo (a mean decline of 0.26 mL/ min/1.73 m2). The decrease was mainly observed during the initial six weeks of the trial, after which a further slight, but significant, decline in eGFR occurred in the telmisartan group.
“In TRANSCEND we enrolled patients with normal urine protein excretion—at least not more than microalbuminuria—and most of them had pretty good renal function, so not much happened, and if something happened it was not different from the placebo group,” Dr. Mann said.
Longer Follow-up Needed
While the strength of the study is that it is the largest trial to date to examine renal outcomes in patients with atherosclerosis receiving an ARB versus placebo, the relatively low number of such outcomes is its main limitation, Dr. Mann added.
“The original sample size estimates for the trial were based on a composite cardiovascular outcome and not on renal outcomes,” the authors wrote. “Our primary analysis used a time-to-event approach and included all randomly assigned patients.”
A study with longer follow-up could potentially lead to a different conclusion than that demonstrated in TRANSCEND, said Katherine R. Tuttle, MD, when asked to comment on the study in a phone interview. Dr. Tuttle, who was not involved with the study, is Medical and Scientific Director at Providence Medical Research Center/Sacred Heart Medical Center and Clinical Professor of Medicine in the Division of Nephrology at the University of Washington School of Medicine.
“Arguably, perhaps for people at high risk who don't yet have overt disease, maybe there would be benefits if we had a very long-term study that went far enough out to see what happens. [In TRANSCEND] there weren't very many people who developed end-stage renal disease or even doubled their creatinine, so some people might say you have to wait longer to see the benefits, but we don't know that. That's pure speculation.”
Nevertheless, TRANSCEND is a large, well-designed trial, Dr. Tuttle said.
“I think we're learning that we can't extrapolate from trials of patients with overt kidney disease to necessarily other populations who are treated with angiotensin receptor blockers in terms of their effects on the kidney.”
Albuminuria and Kidney Function
The study points out another area for further exploration—urinary albumin excretion as a marker of renal function, the authors noted. In the study, telmisartan reduced albuminuria, but individuals who had a reduction in GFR also had a reduction in albuminuria.
“We've typically believed that higher levels of albuminuria predict loss of kidney function, and that is true in the people that those of us in nephrology tend to study, which is people with overt kidney disease and heavy proteinuria,” Dr. Tuttle said.
“But in these people with lower levels of albuminuria who were treated with an ARB, that reduction in albuminuria didn't necessarily predict better kidney function, but in fact they had less of an increase [in albuminuria] with more of a decrease in GFR. That argument that it's going to be a marker of kidney function across all stages of disease is open to question.”