by Dr Geoffrey Modest<\/p>\n
One concern about patients having heart failure with preserved ejection fraction (HFpEF) is the dearth of effective treatments for long-term outcomes in this quite common problem. One of the most influential studies was the\u00a0TOPCAT study<\/a>, which\u00a0found a nonsignificant benefit for spironolactone. A subsequent post hoc\u00a0analysis (see\u00a0<\/strong>below), however, found a significant outcome benefit\u00a0\u200b from spironolactone\u00a0in those patients enrolled from\u00a0the United States, Canada, Brazil, and Argentina (the Americas) but not in those from Russia and Georgia.<\/p>\n Details, in brief, of TOPCAT:<\/p>\n — 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 a diuretic,\u00a0ACE-I\/ARB, and\/or 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,\u00a0was improved a bit (12% vs 14%)<\/p>\n <\/p>\n But in 2015\u00a0there 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\/Georgia was so much lower than in the Americas (see Pfeffer MA. Circulation. 2015;131:34), finding:<\/p>\n — there was an unusually large, greater than fourfold, increase in primary outcomes in the patients in\u00a0the Americas vs those\u00a0in Russia\/ Georgia, being 11.5 per 100 patient-years in the Americas vs 2.4 per 100 patient-years in Russia\/Georgia. — review of all of the different cardiovascular outcomes assessed found a highly significant difference in the spironolactone groups in 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\u00a0(suggesting they were taking more\u00a0spironolactone there)\u200b<\/p>\n –My understanding is that these regional\u00a0inconsistencies 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\u00a0recent AHA guidelines <\/a>endorsing\u00a0the use of\u00a0spironolactone in HRpEF (a Grade IIb recommendation, moderate level of evidence)\u200b<\/p>\n <\/p>\n And, a new analysis just came out\u00a0assessing the serum canrenone levels (metabolite of spironolactone) in the stored serum specimens (see de Denus, S. N Engl J Med 2017; 376: 1690):<\/p>\n –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.<\/p>\n –of the patients assigned to spironolactone who\u00a0reported taking the drug at the 12-month visit (76 of 101 patients from the US\/Canada; 66 of 70 patients from Russia):<\/p>\n –canrenone concentrations were undetectable in 30% of the Russian group<\/strong> and 3% of the US\/Canada (p<0.001)<\/p>\n –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<\/p>\n \u200b–only those who had canrenone detected from both areas had significant increases in serum potassium and aldosterone levels (as anticipated)<\/p>\n <\/p>\n So, all of this shows a few things:<\/p>\n –it is undoubtedly quite difficult to have equal quality control at 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 from the different sites, as in this study<\/p>\n –spironolactone seems to\u00a0actually modify disease progression\/associated cardiovascular effects, which is really important since not much else seems to help. The TOPCAT study tried to deal with the often difficult problem of making sure the patients\u2019 symptoms were actually from the HFpEF (as opposed to being from the\u00a0comorbidities, which it can be hard to differentiate from those related to those from\u00a0HFpEF itself), by enrolling patients who had a recent hospitalization predominantly for heart failure or those with high natriuretic peptide levels (and those specifically\u00a0who had high natriuretic peptide levels on subgroup analysis did show benefit from spironolactone). And diuretics overall\u00a0help the heart failure symptoms, as well as treating underlying associated conditions (hypertension, atrial fib, myocardial ischemia, hyperlipidemia)<\/p>\n –my experience is also that spironolactone is a good augmenter of loop diuretics (I am treating a 93 yo patient with pretty severe symptomatic HFpEF, on torsemide 50mg but still symptomatic and with BNP of 639; I switched his diuretic therapy to torsemide 30mg and spironolactone 25 mg with quite dramatic clinical improvement and rapid decrease in BNP to 461, with further therapy limited by low blood pressure).<\/p>\n 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. And, it raises even further my respect for spironolactone — also seems to be a really potent agent in those with refractory hypertension<\/a><\/p>\n <\/p>\n","protected":false},"excerpt":{"rendered":" Spironolactone helps heart failure with preserved EF […]<\/p>\n
\n— further breakdown showed that even in the placebo group, the respective numbers were 12.6 per 100 patient-years in the Americas and 2.5 per\u00a0100 patient-years in Russia\/Georgia; and in the spironolactone group were 10.4 versus 2.3 per 100 patient-years– in the Americas, the\u00a0primary composite event rate was actually a significant 18% lower in those on spironolactone, HR 0.82 (0.69-0.98); though in Russia\/Georgia was nonsignificantly\u00a0higher at HR 1.10 (0.79-1.51)<\/p>\n