No additional benefit from intensive vs conventional BP lowering on progression to ESRD

Susan Jeffrey

March 15, 2005

London, UK - Results of a new randomized trial show that in patients already receiving the ACE inhibitor ramipril, more intensive additional therapy with the calcium antagonist felodipine did lower blood pressure more effectively than ramipril alone, but no benefit of the more-intensive regimen was seen in residual proteinuria, decline in the glomerular filtration rate (GFR), or progression to end-stage renal disease (ESRD).

The results, from the second Ramipril Efficacy in Nephropathy (REIN-2) study, are published in the March 12, 2005 issue of the Lancet[1].

"Altogether, these data suggest that further blood-pressure reduction below usual targets with felodipine given with a fixed ACE-inhibitor dose does not confer additional renoprotection," the researchers, with principal investigator Dr Giuseppe Remuzzi (Mario Negri Institute for Pharmacological Research, Bergamo, Italy), conclude. "They also extend previous evidence that dihydropyridine calcium-channel blockers, unlike ACE inhibitors or angiotensin-II-receptor blockers, do not offer additional renoprotection."

First author on the paper is Dr Piero Ruggenenti (Mario Negri Institute for Pharmacological Research).

No additional benefit

In both diabetic and nondiabetic chronic nephropathies, the researchers write, high blood pressure is a major determinant of disease progression, and BP reduction is renoprotective. In the first REIN-1 study, these researchers reported that at comparable levels of blood-pressure control, the ACE inhibitor ramipril slowed decline in GFR and reduced progression to ESRD by 50% compared with conventional drugs in patients with nondiabetic renal disease[2].

Some studies have suggested an additional benefit from more aggressive blood-pressure lowering on top of ACE-inhibitor therapy, but one meta-analysis of 11 trials suggested that reducing systolic BP to less than 120 mm Hg did not provide further renoprotection over systolic pressures of 120-130 mm Hg, and when the systolic pressure fell below 110 mm Hg, renal disease even appeared to be accelerated[3]. "Thus, the additional benefit of blood-pressure reduction to lower than the original REIN study targets remains questionable and might even create safety issues," the authors note.

In REIN-2, Ruggenenti et al randomized 338 patients with nondiabetic proteinuric nephropathy on background therapy of 2.5 to 5 mg/day of ramipril to either conventional (diastolic <90 mm Hg) or intensified (systolic/diastolic <130/80 mm Hg) blood-pressure control. To achieve the intensified target, patients received add-on therapy with felodipine. The primary outcome was time to ESRD.

Three of these patients never took the study drug and were excluded. After a median follow-up of 19 months, the study was stopped for futility when interim analysis showed that there was no significant difference in the number of those in the intensified or conservative group who progressed to ESRD.

REIN-2: Primary end point

Measure Intensified BP control, n=167 Conventional BP control, n=168 Hazard ratio (95% CI) p
Time to ESRD, n (%) 38 (23) 34 (20) 1.00 (0.61-1.64) 0.99

No differences were seen in the rate of decline in the GFR, the median rate of decline in creatinine clearance, or in urinary protein excretion between groups. There were five deaths in the study, three in the conservative group (one MI, one stroke, one cancer) and two in the intensive BP-lowering group (one MI and one death from unknown causes).

There were 25 nonfatal serious adverse events in the conventional control group and 37 in the intensive control group; there were no cases of severe hypokalemia reported.

Blood pressure or albuminuria target of therapy?

In an editorial accompanying the paper, Drs Paul E De Jong and Dick de Zeeuw (University Medical Center, Groningen, the Netherlands) point out that Ruggenenti et al showed that felodipine was not renoprotective on a background of ACE-inhibitor therapy, a "remarkable" finding because felodipine did lower systolic and diastolic pressures by 4 and 3 mm Hg respectively[4]. However, they caution that the authors did not show that lowering BP further is of no benefit, only that lowering BP further with felodipine is not of further renal benefit. "It is not wise to extrapolate their finding with one specific agent that lowers blood pressure to the general conclusion that further lowering of blood pressure would not be of additional renal benefit," De Jong and de Zeeuw write. "Such a conclusion could, in daily practice, wrongfully lead to therapeutic idleness."

However, the finding presents a dilemma, since dose adjustments and adding other drugs to better protect the kidneys is still titrated on blood pressure. They suggest that, instead, perhaps these decisions should be based on the effect of treatment on urinary albumin excretion. "Indeed, the less albumin in the urine, the more renoprotection in the long run, both in diabetic and nondiabetic renal disease," they write. "It is thus not unexpected that the regimen with felodipine, which did not decrease urinary albumin excretion, did not prevent progression to end-stage renal disease."

Albuminuria may be a manifestation of generalized endothelial dysfunction, atherosclerosis, or both, they write, and screening for it might therefore detect patients at risk for progressive atherosclerosis that will ultimately result in renal and cardiac failure. Treatment with an ACE inhibitor, then, may help to prevent not only renal but cardiac failure.

"The evidence that lowering of overt proteinuria might prevent both renal and cardiac failure should now be extrapolated to patients with microalbuminuria," they conclude. "The renoprotective effect of a drug should not only be tested by its ability to lower blood pressure but also by its effect on decreasing urinary albumin excretion."


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