978-1-4377-0398-6
Update Type
Slide Deck? / Late Breaking Clinical Trial
YESNO
Title / AHA 2013: TOPCAT: Spironolactone treatment in patients with HFpEF
Date / November 18, 2013
Embargo time / lifted
Writer / Debra L. Beck
Slide Deck Name / Please provide Slide Deck Title
Presenter Credentials / [Author First Last], [Credentials] on behalf of [Study Group]
Braunwald Placement / 4-u1.0-B978-1-4377-0398-6..00080-9--p1170
Companion Placements / Antman / 4-u1.0-B978-1-4557-0101-8..00012-6--p0855
Ballantye
Black
Blumenthal
Creager
Issa, 2e
Mann / 4-u1.0-B978-1-4160-5895-3..10048-8--p0205
Kormos
Otto
Theroux
Reference List / AHA 2013 Late-Breaking Clinical Trial: TOPCAT: Treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT). Presented by MA Pfeffer on November 18.
Please enter the update text in the space below:
Mineralocorticoid receptor antagonists (MRAs) have proven benefits in patients with heart failure with reduced ejection fraction, as seen in the RALES and EMPHASIS trials. The objective of the TOPCAT trial was to determine if treatment with spironolactone can produce a clinically meaningful reduction in the composite endpoint of cardiovascular mortality, aborted cardiac arrest, or heart failure (HF) hospitalization, compared with placebo, in adults with heart failure with preserved ejection fraction (HFpEF).
Eligible participants had symptomatic heart failure, an ejection fraction of 45% or greater, and had to have either a hospitalization within the past year for management of HF or elevated natriuretic peptides (BNP ≥100 pg/mL or NT-proBNP ≥360 pg/mL). Those with reduced renal function, uncontrolled hypertension, atrial fibrillation with a rate >90/min, a recent ACS, or cardiomyopathy were excluded.
TOPCAT was an international, 270-center, double-blind, placebo-controlled trial. Patients (n=3445) were randomized 1:1 to either spironolactone with a target dose of 30 mg daily (titration up or down, as needed) or matching placebo. Mean LVEF was 56%. Most participants achieved eligibility for the study based on a recent HF hospitalization (71.5%), with the remainder (28.5%) being eligible based on elevated natriuretic peptide levels (NPs).
Representative of a typical HFpEF population, 91.5% of patients were hypertensive, about 60% had coronary artery disease, and 26% had experienced a previous myocardial infarction.
The mean dose of spironolactone at 8 months was 25 mg in the spironolactone arm (28 mg in the placebo arm). At the end of 3 years, 34.3% of the spironolactone arms were no longer taking their study medications, as were 31.4% of the placebo arm. Just fewer than 4% of both arms were lost to follow-up.
There was no difference in the primary endpoint of cardiovascular death, HF hospitalization, or resuscitated cardiac arrest (18.6% for spironolactone and 20.4% for placebo; hazard ratio; 0.89; p=0.138). Mortality between arms did not differ, nor did the occurrence of cardiac arrest, but the HF hospitalization rate was lower in the study arm at 12.0%, compared to 14.2% for placebo (HR, 0.83; p=0.042).
All-cause hospitalization did not differ between groups, nor did the rates of serious adverse events. However, hyperkalemia was more common with spironolactone (18.7% vs. 9.1% for placebo; p<0.001) as was the rate of doubling above the upper limits of normal of creatinine (HR, 1.49; p<0.001). Despite these findings, there were no reports of death from hyperkalemia, no difference between groups in the probability of having a creatinine level ≥3.0 mg/dl (HR, 1.06; p=0.697), or the need for dialysis.
Only one of 22 prespecified subgroup analyses, showed a significant interaction by treatment: there was an “appearance” of a benefit in those patients who entered the study based in elevated NPs for the primary composite endpoint (15.9% for spironolactone vs. 23.6% for placebo; HR, 0.65; p=0.003).
The investigators concluded that treatment with spironolactone in HFpEF did not alter the incidence of the composite endpoint of cardiovascular death, resuscitated cardiac arrest, or HF hospitalization. Reductions in HF hospitalization were observed and the use of spironolactone is associated with hyperkalemia and increased creatinine and requires careful monitoring of patients.
In her discussion of the results of TOPCAT, Dr. M Redfield stressed that the rationale for TOPCAT was “extremelystrong,” not just because of the results seen in HFrEF patients, but because evidence shows that aldosterone levels in HFpEF are associated with mortality. “Also, all the conditions that are so common in HFpEF, hypertension, diabetes, atherosclerosis, renal dysfunction, high sodium diet, that these factors drive myocardial oxidative stress, which can activate the cardiac MR receptors, independent of aldosterone levels,” she explained. Slow enrollment necessitated a redesign of the study, with longer follow-up, she explained, speculating that perhaps had the study ended at 36 months—remember that RALES and EMPHASIS were stopped early, at about 24 months, because of clear benefit—the trial might have shown a significant benefit for the study drug. She also noted the large percentage of patients who discontinued their study medications towards the end of the trial as a possible reason for the lack of significance. On the other hand, she noted that there was no reduction in all-cause hospitalization and that the trends towards worsening renal function and hyperkalemia may be more common and more problematic in clinical practice than in the “highly monitored environment of a clinical trial.”
“I think there was a clear signal of benefit in this trial, and I think that the subgroup analysis presented was very appropriate and compelling and suggest that there may be a subgroup of patients, the more high-risk group of patients, that could benefit from this class of agents,” she said.