Spironolactone appears to reduce albuminuria and improve outcomes in heart failure patients with preserved ejection fraction (HFpEF), according to a new study.
Increasing values of urinary albumin-creatinine ratio (UACR) are tied to higher risks for major cardiovascular events and worsening renal function in patients with HFpEF, but no therapies to date have reduced their albuminuria.
“Reducing albuminuria was independently associated with improved prognosis, including a reduction in mortality risk. Blood pressure reduction was related to albuminuria reduction, but blood pressure reduction did not explain the mechanism by which spironolactone reduced albuminuria,” Dr. Senthil Selvaraj of the Hospital of the University of Pennsylvania, in Philadelphia, told Reuters Health by email.
The findings were published online November 11 in Circulation to coincide with a presentation at the 2018 American Heart Association (AHA) Scientific Sessions in Chicago.
Dr. Solomon and his colleagues analyzed data from 1,175 participants treated in the Americas who participated in the TOPCAT international double-blind trial of spironolactone in adults over 50 years of age with HFpEF and urinary UACR tests at baseline. Participants were recruited at over 270 clinical sites over a six-year period and followed for an average of 3.5 years.
The researchers investigated the link between UACR with the primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) and with all-cause mortality and safety endpoints, using multivariable-adjusted Cox regression. All participants were asked to provide a spot urine specimen that was tested for chemistries, including UACR, at baseline and once a year thereafter.
In a subpopulation of 744 patients, the authors monitored whether spironolactone decreased albuminuria at one year. Overall, 35% of patients had microalbuminuria, 13% had macroalbuminuria, and 80% were being treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.
Participants with increasing UACR were more likely to be male and have higher systolic blood pressure, diabetes mellitus and kidney dysfunction. Compared with normoalbuminuria, macroalbuminuria (hazard ratio, 1.67) and microalbuminuria (hazard ratio, 1.47) were independently linked with the study’s primary end point.
At one year, after adjustments for placebo response, spironolactone reduced albuminuria by 39% in all participants compared with baseline data and by 76% in patients with macroalbuminuria, regardless of their comorbidities or medications.
Reducing UACR by 50% was independently linked with a 10% drop in heart-failure hospitalization (P=0.017) and a 9% drop in all-cause mortality (P=0.019).
The change in UACR was significantly linked with systolic blood pressure change (P=0.001).
“Albuminuria is present in roughly half of patients with HFpEF and its presence portends worse prognosis, but effective therapies to treat HFpEF are limited,” Dr. Selvaraj explained. “Thus, novel approaches to reduce morbidity are in urgent need. Our results provide a physiological rationale for the use of spironolactone in patients with HFpEF.”
“Of note,” Dr. Selvaraj added, “the original TOPCAT study did not reach its primary endpoint, potentially due to study misconduct detected in Russia and the country of Georgia; therefore, our results support the reappraisal of spironolactone in ongoing randomized trials of HFpEF.”
Senior author Dr. Scott Solomon of Brigham and Women’s Hospital and Harvard Medical School in Boston said by email, “Spironolactone is an effective adjunct therapy to reduce albuminuria in patients with diabetic nephropathy. Thus, we hypothesized that spironolactone may have a benefit in HFpEF patients, generally speaking, but interestingly, we showed that several subgroup analyses, including non-diabetics, derived similar benefit.”
The National Heart, Lung, and Blood Institute funded the study.
—Lorraine L. Janeczko