This may be the first drug shown to reduce mortality in the HFpEF population in the United States but will hopefully not be the last.
Cardiovascular disease continues to be the No. 1 cause of mortality in the western world, including the United States.1 Heart failure is a main contributor to cardiac-related mortality. Of the patients newly diagnosed with heart failure, about 50% will not survive more than 5 years.2 The mortality and hospitalization rates are fairly similar for patients with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).3 About 50% of all heart failure patients have preserved ejection fraction defined as an ejection fraction ≥50%.
Pharmacologic therapies have not been shown to improve mortality in HFpEF, unlike therapies in HFrEF.3 This includes the cornerstone of HFrEF therapy angiotensin converting enzyme (ACE) inhibitors, as well as angiotensin receptor blockers (ARBs) or beta blockers. Recent evidence, however, advocates for the use of aldosterone antagonists, such as spironolactone in HFpEF.
The Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) study was an international, randomized, double-blind, placebo-controlled trial.4 Patients with an ejection fraction ≥45% with either a heart failure hospitalization within 12 months before randomization or an elevated brain natriuretic peptide (BNP; BNP ≥100 pg/mL or N-terminal pro-BNP ≥360 pg/mL) within 60 days before randomization were included. Patients were then randomized to either placebo or spironolactone. Patients were recruited from North and South America as well as Russia and Georgia. After more than 3 years of follow-up, in the 2 cohorts that were similar, there was no difference in the composite of mortality from cardiovascular causes, hospitalization for heart failure, or resuscitated cardiac arrest with spironolactone. A significant reduction in heart failure hospitalizations, however, was noted in the spironolactone cohort.
A post-hoc analysis of TOPCAT found significant variations in the 2 populations studied. Not only were baseline demographics significantly different, but the patients from Russia/Georgia had an approximately 4-fold decrease in events compared with the patients from the Americas whose rates mirrored those from previous HFpEF trials.5 As a result, when looking just at the North and South American population, the use of spironolactone significantly reduced the composite primary end point as well as singular end points, such as cardiovascular mortality, all-cause mortality, recurrent heart failure, and heart failure hospitalizations.
Further analysis showed that in those Russian patients who consented to have blood levels measured of canrenone, the active metabolite of spironolactone, the levels were undetectable in 30% of patients compared with just 3% in the United States (P<0.001).6 Those patients with detectable metabolite levels had higher incidences of hypekalemia, which mirrored the increase in potassium seen in the original trial in the North and South American population.5
As a result of these data, many have argued that the true effect of spironolactone was not seen in the Russia/Georgia population and thus, the original TOPCAT trial results cannot be applied to the general population. Instead clinicians, especially in the United States, should only be looking at the data from the Americas to make clinical decisions. The newest heart failure guidelines seem to agree with that mindset. The recent American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines published this year state that in select HFpEF patients, the use of spironolactone may be considered to reduce hospitalizatons.7 A weak grade recommendation (IIb) is given with a moderate quality of evidence. There is further discussion in the guidelines regarding the regional variations in TOPCAT, but until confirmatory studies are done in a randomized fashion, the guidelines will not rely on the post-hoc analysis to make a full recommendation for use to reduce mortality.
Clinicians in the Americas should be aware of the regional variations with the TOPCAT trial and strongly consider utilization in their HFpEF patients who meet criteria based on the trial and newest guidelines. If spironolactone is used, then careful monitoring should be undertaken of potassium levels and renal function. This may be the first drug shown to reduce mortality in the HFpEF population in the United States, but it will hopefully not be the last. Ongoing studies are testing the combination of sacubitril/valsartan for HFpEF, as well as other therapies, which makes HFpEF a disease state to closely monitor in the coming years.
1. National Center for Health Statistics. Health, United States, 2016: with chartbook on long-term trends in health. https://www.cdc.gov/nchs/data/hus/hus16.pdf. Published May 2017. Accessed August 25, 2017.
2. Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30-41. doi: 10.1038/nrcardio.2010.165.
3. Redfield MM. Heart failure with preserved ejection fraction. N Engl J Med.2016;375(19):1868-1877.
4. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383—92. doi: 10.1056/NEJMoa1313731.
5. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial. Circulation. 2015;131:34-42. doi: 10.1161/CIRCULATIONAHA.114.013255.
6. de Denus S, O'Meara E, Desai AS, et al. Spironolactone metabolites in TOPCAT - new insights into regional variation. N Engl J Med. 2017;376(17):1690-1692. doi: 10.1056/NEJMc1612601
7. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2017;70(6):776-803.