Aldo-Antagonist Falls Short but Impresses in Preserved-EF Heart Failure: TOPCAT

November 18, 2013

DALLAS, TX — A randomized clinical trial in patients with HF with preserved ejection fraction (HFPEF) has its researchers and some experts hopeful that there may finally be a drug for the disorder that can improve clinical outcomes.

The study was negative, all agree: patients who took the aldosterone inhibitor spironolactone failed to show benefit for the clinical composite primary end point. But they did have significantly fewer heart-failure hospitalizations, a part of the primary end point, over the average follow-up of 3.3 years in the trial, called Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT).

"We have an important finding here," said Dr Marc A Pfeffer (Brigham and Women's Hospital, Boston, MA) in a presentation for the media here at the American Heart Association 2013 Scientific Sessions . Pfeffer also gave the TOPCAT formal presentation at a late-breaking clinical-trials session today. Although the primary end point wasn't met for the trial's overall population, "we're very confident that we've reduced hospitalizations for heart failure."

Also at the briefing, Dr Margaret M Redfield (Mayo Clinic, Rochester, MN) agreed that the trial, "although not statistically significant, showed a signal of benefit." Redfield was later the discussant after Pfeffer's formal presentation.

She cautioned, however, that "overall, all-cause hospitalizations and all-cause mortality did not seem to be meaningfully impacted by this drug. And we have to acknowledge that, minus the careful [creatinine and serum potassium] monitoring that occurred in the clinical trial, the prevalence of worsening renal function and hyperkalemia would likely be more common in clinical practice."

Dr Marc A Pfeffer

Pfeffer and other experts agreed that TOPCAT points to spironolactone as an option for patients with HFPEF as long as those safety issues are addressed. He said he will now use the drug in his HFPEF patients, although it will be up to physicians to decide for themselves. "We have a generic medication that we can show how to use safely and, we do believe, relieves the burden these patients have."

Speaking with heartwire , Dr Clyde Yancy (Northwestern University, Chicago, IL) said, "The first thing about TOPCAT is to acknowledge the study results: they are negative. The second thing is to interpret the results very carefully and realize that there's not a signal, there's actually a message: for the first time we can modify the natural history of heart failure with preserved ejection fraction. And the third is that with the unique prism that I have, as a lifelong practitioner in this space, as someone who writes guidelines and does clinical trials, my deduction, looking at the data from all those difference lenses, is that I will use it as a clinician."

When physicians use it in their HFPEF patients, he agreed on the importance of good safety monitoring, especially for renal function, and recommended clinicians "look carefully for any other reason that would further corroborate the decision to give any aldosterone antagonist, like hypertension, for example."

TOPCAT randomized 3445 heart-failure patients at least age 50 with an LVEF >45% at 270 sites in six countries to receive the aldosterone antagonist or placebo. Spironolactone was titrated up to 30 to 45 mg/day.

Clinical Outcomes in the TOPCAT Trial, Mean 3.3-Year Follow-up

End points Spironolactone (%) n=1722 Placebo (%) n=1723 HR (95% CI P
Primary* 18.6 20.4 0.89 (0.77–1.04) 0.138
CV mortality 9.3 10.2 0.90 (0.73–1.12) 0.354
Aborted cardiac arrest <1.0 <1.0 0.60 (0.14–2.50) 0.482
HF hospitalization 12.0 14.2 0.83 (0.69–0.99) 0.042

*CV mortality, aborted cardiac arrest, or HF hospitalization

There were no significant differences in adverse events, except, Pfeffer emphasized, more hyperkalemia with spironolactone and more hypokalemia on placebo; there were no hyperkalemia-related deaths.

Rates of Hyperkalemia and Hypokalemia in TOPCAT by Treatment Group

End points Spironolactone, n=1722 (%) Placebo, n=1723 (%) p
Hyperkalemia >5.5 mmol/L 18.7 9.1 <0.001
Hypokalemia, <3.5 mmol/L 16.2 22.9 <0.001

Interestingly, in a post hoc analysis of outcomes across the six countries, there was something of an East-West divide. The primary end point hazard ratio (HR) just for the four Western-hemisphere nations—the US, Canada, Brazil, and Argentina, contributing 51% of the trial's patients—was 0.82 (95% CI 0.69—0.98). It was 1.10 (95% CI 0.79—1.51) solely for the remaining TOPCAT countries of Russia and the Republic of Georgia.

Dr Margaret M Redfield

Events on placebo varied dramatically by region, Pfeffer said. In North and South America, it was 31.8%, and in Russia and the Georgian Republic it was 8.4%. "We feel that the event rate in the Americas is more reflective of the burden these patients feel." So he and his colleagues felt it was important to present the findings, Pfeffer said, acknowledging that with post hoc analyses, "you're on statistical thin ice."

Redfield said she agreed that "the regional variation noted post hoc could have affected the results of the trial"; that is, had there been none, the primary results might have been stronger.

Pfeffer discloses receiving research grants from Amgen, Celladon, Novartis, and Sanofi; consulting or serving on an advisory board for Aastrom, Amgen, Bristol-Myers Squibb, Cerenis, Concert, Genzyme, Hamilton Health Sciences, Keryx, Medtronic, Merck, Novartis, Roche, Servier, University of Oxford, Xoma, and Teva. "Brigham & Women's Hospital has patents for use of inhibitors of the renin-angiotensin system in selected survivors of MI. Dr Pfeffer's share of the licensing agreement with Novartis is irrevocably transferred to charity." Redfield had no disclosures.

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