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Serelaxin improved renal blood flow in chronic HF patients
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ORLANDO, Fla. — Results of a small, randomized, exploratory study suggest that serelaxin signals a potential renal benefit in patients with chronic HF.
Serelaxin, also known as RLX030 (Novartis), is a novel recombinant form of the human hormone relaxin-2.
According to data presented at the Annual Scientific Meeting of the Heart Failure Society of America, serelaxin 30 mcg/kg per day was associated with improved renal blood flow of 29% from baseline over 8 to 24 hours, and placebo was associated with a 14% improvement. Compared with placebo, serelaxin increased renal blood flow over 8 to 24 hours by 13% (P=.0386).
Change in glomerular filtration rate (GFR), another primary endpoint of the trial, was not significantly different over 8 to 24 hours between the groups (P=.39).
Adriaan A. Voors
“A bit to our surprise, we didn’t find any response in GFR [with serelaxin]. There was no worsening, no improvement, no effect whatsoever on GFR,” Adriaan A. Voors, MD, PhD, of the department of cardiology at the University Medical Center Groningen, the Netherlands, said at a late-breaking clinical trials session.
Observed as one of the secondary endpoints in the trial, serelaxin was associated with a 16% relative reduction in filtration fraction over 8 to 24 hours compared with placebo (P=.0019). Systolic BP remained constant in both groups during the study period, whereas the serelaxin group had decreased diastolic BP at 4 and 8 hours compared with the placebo group. There were no differences in urinary flow rate and creatinine clearance, Voors said.
The study was designed to assess the effects of serelaxin (n=39) on renal hemodynamics as compared with placebo (n=48). Researchers enrolled 87 patients with chronic HF (mean age, 68 years; 89% men). The patients’ mean estimated GFR was 64 mL/min/1.73m2; left ventricular ejection fraction was ≤45%; brain natriuretic peptide was ≥100 pg/mL or N-terminal pro–B-type natriuretic peptide was ≥400 pg/mL; and all had NYHA Class II or III HF. Renal tracer results were implausible in 22 patients, so the primary analysis was performed using 65 patients (serelaxin, n=28; placebo, n=37).
The drug was well tolerated, and there was no difference in rate of adverse events (20.5% with serelaxin vs. 25% with placebo).
“Overall, these results indicate beneficial effects of serelaxin on renal hemodynamics in chronic HF patients,” Voors said. – by Erik Swain
For more information:
Voors AA. Abstract #A2202. Presented at: the Annual Scientific Meeting of the Heart Failure Society of America; Sept. 22-25, 2013; Orlando, Fla.
Disclosure: The study was funded by Novartis. Voors reports no relevant financial disclosures.
Perspective
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Javed Butler, MD, MPH
One of the signals we saw in RELAX-AHF, a trial of serelaxin in patients with acute HF, was preservation of kidney function in terms of cystatin-C levels. This study takes it to the next level in a more mechanistic way as we try to understand why serelaxin may have a beneficial effect on the kidneys. What we saw in this renal mechanistic study was a substantial improvement in renal plasma flow with the use of serelaxin over placebo. That does have the potential impact of improving kidney function in patients with acute HF, and that may translate into improved outcomes.
That it didn’t affect the GFR is a signal that the kidneys don’t have to work as hard. Although the GFR was maintained, the filtration fraction was reduced. As we know, there are a lot of intraglomerular hemodynamic changes that occur in patients with HF, and especially in acute HF, to increase filtration fraction in order to maintain the GFR. So the fact that filtration fraction went down and the GFR was maintained, related to increase in blood supply, suggests easing of the burden on the kidneys.
This field is incredibly important. For the past 20 years, when patients with acute HF come into the hospital, they have an approximately 30% chance of dying within 1 year. Unfortunately, many patients and providers may not fully appreciate this fact. Right now, we have not a single approved therapy for patients with acute HF that has been shown to reduce postdischarge mortality. So drugs like this and studies like this are critically important for us to understand and move the field forward. Hopefully, we can bend the curve.
Perspective
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Uri Elkayam, MD
Serelaxin is an exciting new drug and the results of the clinical trials are very promising. The beneficial effect of the drug is most probably related to its vasodilatory effect. The concept of vasodilation in HF makes great clinical sense. Drugs such as nesiritide (Natrecor, Scios) and nitroglycerin have a potent hemodynamic effect and definitely provide symptomatic improvement to individual patients. Unfortunately, for a variety of reasons, including drug dosing, timing of administration and heterogeneous patient population, nesiritide in the ASCEND-HF trial did not live up to expectations and failed to improve symptoms and outcome. Nitroglycerin, which is widely used, has never been evaluated properly and therefore many questions regarding its efficacy, including its effective dose and the impact of nitrate tolerance, as well as regarding its safety and side effects, still need to be answered in a large randomized trial.
Because of the above-mentioned limitations of existing vasodilators, the positive signals we’re getting from the studies of serelaxin in acute HF are really encouraging. This time, the dose of the drug was carefully selected; also, it was given early after hospitalization and to patients with preserved BP. The studies have shown a favorable side-effect profile, improvement of symptoms and even a positive effect on long-term outcomes. The effect on the kidney is an important part of the therapeutic effect or action of any drug used for this indication. Serelaxin was found to increase renal blood flow without a change in renal function or urinary volume. Though this is somewhat disappointing, and suggests that the renal effect of serelaxin is not the main cause for its beneficial clinical effects, at least the drug seems renal-friendly and it should not have any untoward renal effects.
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