Spironolactone helps heart failure with preserved EF

One concern about patients with heart failure and preserved ejection fraction (HFpEF) is the dearth of effective treatments for long-term outcomes. One of the most influential studies was the TOPCAT study, which found a nonsignificant benefit (see http://gmodestmedblogs.blogspot.com/2014/04/spironolactone-in-diastolic-heart.html  for a review of the TOPCAT trial). A subsequent post hoc analysis, however, (see below) found a fourfold difference and significant benefit ​in outcomes from spironolactone between those patients from the United States, Canada, Brazil, and Argentina (the Americas) versus those from Russia and Georgia.

Details, in brief, of TOPCAT:

-- 3445 participants with symptomatic HFpEF (EF>45%) were randomized to spironolactone vs placebo, mean dose 28mg/d, followed 3.3 years, around 80% also on diuretic, ACE-I/ARB, b-blocker, finding no difference in the primary outcome of the combination of cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure. But the rate of hospitalization, as an isolated outcome, was improved a bit (12% vs 14%)

 

But in 2015 there was an article looking more directly at the regional variations in outcomes of the study, spurred on by the fact that the event rate in the placebo group in Russia and Georgia was so much lower than in the Americas (see chf preserved EF spironolac helps circ2015  in dropbox, or Pfeffer MA. Circulation. 2015;131:34), finding:

-- there was an unusually large, greater than fourfold, increase in primary outcomes in the patients in the Americas vs those in Russia and Georgia versus, being 11.5 per 100 patient-years in the Americas and 2.4 per hundred patient-years in Russia/Georgia.

-- Further breakdown showed that in the placebo group, the respective numbers were 12.6 per 100 patient-years in the Americas and 2.5 per 100 patient-years in Russia/Georgia; and in the spironolactone group were 10.4 versus 2.3 per 100 patient-years

-- in the Americas for a primary composite event rate was a significant 18% lower in those on spironolactone, HR 0.82 (0.69-0.98); though in Russia/Georgia was nonsignificantly higher at HR 1.10 (0.79-1.51)

-- review of all of the specific cardiovascular outcomes showed a highly significant difference in the spironolactone group comparing the regional differences of these 2 areas, with almost all having p<0.001. Of note, there was also a much more significant increase in creatinine above 3.0 mg/dL, and lack of hypokalemia with potassium <3.5 mmol/L , in the Americas only (suggesting they were taking more spironolactone there)​

--my understanding is that these regional inconsistencies in the TOPCAT study, with the significant benefit in the Americas wing and suspicions about the accuracy of the Russia/Georgia group, led to the recent AHA guidelines endorsing the use of spironolactone (see http://gmodestmedblogs.blogspot.com/2017/05/new-heart-failure-guidelines.html  , a Grade IIb recommendation, moderate level of evidence)​

 

And, a new analysis just came out showing that assessed the serum canrenone levels (metabolite of spironolactone) in the stored serum specimens (see de Denus, S. N Engl J Med 2017; 376: 1690):

--206 patients from the US and Canada, and 160 patients from Russia had serum samples to assay; these people were representative of the overall TOPCAT populations from the different regions.

--of the patients assigned to spironolactone who reported taking the drug at the 12-month visit (76 of 101 patients from the US/Canada; 66 of 70 patients from Russia):

    --canrenone concentrations were undetectable in 30% of the Russian group and 3% of the US/Canada (p<0.001)

    --a significant correlation was found in the US/Canada between doses of spironolactone that people said they were taking and the canrenone concentration; no correlation for the Russian group

    ​--only those who had canrenone detected from both areas had significant increases in serum potassium and aldosterone levels (as anticipated)

So, all of this shows a few things:

--it is undoubtedly quite difficult to have equal quality control in different sites of care, and this is no doubt aggravated in different countries/cultures. Which means that we, as readers of these studies, should maintain a healthy skepticism regarding the results, especially when they are so discordant as in this study

--spironolactone works in terms of actually modifying disease progression/associated cardiovascular effects, which is really important since nothing else seems to help. The TOPCAT study tried to deal with the difficulty in making sure the patients symptoms were actually from the HFpEF (as opposed to being from the comorbidities, which is can be hard to differentiate from those related to the HFpEF), by enrolling patients who had a recent hospitalization predominantly for heart failure, or those with high natriuretic peptide levels (actually in the TOPCAT study, those who had high natriuretic peptide levels on subgroup analysis did show benefit from spironolactone). And diuretics overall help, as well as treating underlying associated conditions (hypertension, atrial fib, myocardial ischemia, hyperlipidemia)

--my experience is also that spironolactone is a good augmenter of loop diuretics (a 93 yo patient with pretty severe symptomatic HFpEF, on torsemide 50mg but still symptomatic and with BNP in the 500 range; I switched his diuretic therapy to torsemide 30mg and spironolactone 25 mg with pretty dramatic clinical improvement and decrease in BNP to 200, with further therapy limited by low blood pressure).

--these studies therefore pretty much confirm that low-dose spironolactone is an important med in patients with symptomatic HFpEF, both in terms of symptomatic improvement (decreasing hospitalizations) and decreasing cardiovascular mortality, confirming guideline recommendations.