heart failure: benefits of combo Rx for HFpEF

 A recent mathematical analysis estimated the benefits of combined medical therapy in heart failure with mildly reduced and preserved ejection fraction (see chf benefits of combo Rx in HFpEF circ2022 in dropbox or DOI: 10.1161/CIRCULATIONAHA.121.058929)

Details:

-- this analysis was based on a few important prior studies:

   -- PARAGON-HF:  assessed 4822 patients having heart failure with preserved ejection fraction (HFpEF) >45% who were randomized to sacubitril-valsartan (97 mg/103 mg twice a day) versus valsartan alone (160 mg twice a day). The primary outcome was a composite of total hospitalization for heart failure and death from cardiovascular causes: almost statistically significantly different, with rate ratio of 0.87 (0.75-1.01), p=0.06.  However, the rate of hospitalizations for heart failure was a statistically significant 15% decrease with rate ratio 0.85 (0.72-1.00); the NYHA HF class improved in 15% of the patients on the sacubitril-valsartan versus 12.6% on valsartan alone, OR 1.45 (1.13-1.86); renal function decline was less prevalent on sacubitril-valsartan versus valsartan: 1.4% versus 2.7%, HR 0.50 (0.33-0.77); and the mean change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) was 1.0 points higher at 8 months on sacubitril-valsartan (the higher, the better on scale 0-100, ie not much change since 5 points is considered clinically meaningful).

   -- TOPCAT: overall 3,445 patients with symptomatic HFpEF (mean LVF 56%). this was an usual trial in that there was not so much benefit of spironolactone in the original trial, but further analysis found that there was a huge regional difference: those patients in Russia and Georgia had markedly lower event rates than those in the Americas (US, Canada, Brazil, and Argentina), there was no impact of spironolactone in the former group, and there were real concerns about the quality of the study done there (eg, no difference in potassium levels in those randomized to spironolactone). in the Americas, 1767 patients randomized to spironolactone had an 18% decrease in the primary composite event rate (cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure), HR 0.82 (0.69-0.98) see  http://gmodestmedblogs.blogspot.com/2017/06/spironolactone-helps-heart-failure-with.html

   -- EMPEROR-Preserved: 5998 patients with class II-IV heart failure and ejection fraction >40% (mean 54%) randomly assigned  to empagliflozin 10mg vs placebo in addition to usual therapy (RAS system inhibitor 81%, sacubitril/valsartan 37%, b-blocker 87%, mineralocorticoid receptor antagonist 37%), with primary outcome of a composite of cardiovascular death or hospitalization for HF being 21% decreased (HR 0.79 (0.69-0.90), p<0.001, equally for those with and without diabetes. Hospitalizations for HF decreased 27%, HR 0.73 (0.61-0.88), p<0.001, but there were more genital/urinary infections and hypotension with empagliflozin  (see https://www.nejm.org/doi/full/10.1056/NEJMoa2107038 )

-- the overall analysis in this mathematical analysis was for time to first cardiovascular death or heart failure hospitalization

-- based on the criteria used in these 3 studies above, they included the following ejection fraction intervals: 45% to 54%, 55% to 64%, and ≥​65% 

-- they used the standard statistical methodology to synthesize the results of these disparate studies into an estimate of benefits of combined therapy, based on the treatment effects of the individual trials

Results:

--The combination of switching to ARNi from an RAS inhibitor (ie, ACE or ARB), adding an MRA (mineralocorticoid antagonist: eg spironolactone), and adding an SGLT-2 Inhibitor (sodium glucose transpoter-2 inhibitor, eg empagliflozin), would be projected to lead to:

    -- combination of  cardiovascular deaths or heart failure hospitalizations:

        -- EF 45%-54%: 51% risk reduction (26 to 68%)

        -- EF 55%-64%: 46% risk reduction (20 to 63%)

        -- EF ≥​65%: no significant difference, HR 1.17 (0.65- 2.10)

    -- cardiovascular deaths:

        -- EF 45%-54%: 52% risk reduction (10 to 74%)

        -- no significant difference for either of the other two  categories

    -- heart failures hospitalizations

        -- EF 45%-54%: 62% risk reduction (33 to 77%)

        -- EF 55-64%: 56% risk reduction (31 to 72%)

        -- EF ≥​65%: no significant difference

Commentary:

--this study calculated that especially in the group with left ventricular ejection fractions in the 45%-64% range, there would likely be benefit from the combination of medications above. This is pretty important, since so many patients are in this category (about ½ of those with heart failure), the go-to meds for those with reduced ejection fraction have been shown so many times to be beneficial, and until recently there have been a dearth of effective therapies for those with HFpEF

-- they did combine those with mildly reduced EF (HFmrEF) in the analysis, a group of patients without lots of studies. But a few comments:

    -- treatment of patients with heart failure with preserved ejection fraction HFpEF is less clearly beneficial than with patients having reduced ejection fraction (HFrEF), with some evidence that those in the midrange but closer to the reduced ejection fraction level respond better to medications.

    --The European Society of Cardiology had the first recommendations on the management of those patients with HFmrEF, defined as 40-50% (See heart failure guidelines europe 2021 in dropbox, or doi:10.1093/eurheartj/ehab368), making the following points:

        -- overall, HFmrEF resembles HFrEF more, with higher levels of underlying CAD than in those with HFpEF, and with similar overall prognosis

        -- those who progress from HFmrEF to HFrEF have a worse survival than if they are stable (ie, deteriorating cardiac function)

        -- there have been no specific trials of ACE, ARBs, b-blockers, MRAs, or ARNIs in those with HFmrEF

        -- there is also no information about physical conditioning/exercise rehab in this group

        -- it is still important to check natriuretic peptides and echocardiograms

    --for a 2017 review of HFmrEF patients, see http://gmodestmedblogs.blogspot.com/2017/11/heart-failure-with-mid-range-ejection.html , where the abbreviation had been HFmEF (HF with mid-range EF)

-- a few comments on those with left ventricular ejection fractions >58% (of note those with higher EFs did not have benefit in the mathematical modeling):

    -- though patients with very high EFs is likely to be due to HFpEF associated with the usual common culprits (hypertension, ischemic heart disease, age, obesity, insulin resistance/chronic inflammatory state, ...), since common things are common, it should be noted that chronic mitral regurgitation is associated with very high measured EFs, since the heart is struggling to effectively pump out blood to the periphery while a large percentage pumped out then regurgitates back into the heart. And these EFs can be into the 70% range or even higher: see https://www.ahajournals.org/doi/10.1161/CIRCIMAGING.113.001251 and https://www.ahajournals.org/doi/10.1161/CIRCIMAGING.114.001675

    -- there are biological reasons that explain why those with EF >58% actually have decreased acute decompensated heart failure and all-cause mortality (eg there seems to be less abnormal LV relaxation in this group): see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4850208/ . so, there can be a discordance between HFpEF and diastolic dysfunction. and clinical events seem to track differently.

-- for some of my concerns about the role of SGLT-2 meds, see http://gmodestmedblogs.blogspot.com/2022/05/ahaacc-guidelines-on-heart-failure.html . it was notable in the empagliflozin trial above (EMPEROR-Preserved trial) that there was no mention of the use of loop diuretics (furosemide, torsemide) in either the article or the supplementary material, which clearly do work clinically to treat HFpEF. Is there actually any benefit of using the fixed-dose of the new-kid-on-the-block empagliflozin vs the tried-and-true titratable loop diuretics, which work well and seem to have fewer severe adverse effects???

Limitations:

-- the main one: this study assessed the relative roles of the different medications for patients with mildly reduced or preserved ejection fractions and developed a mathematical model to predict the combined role of these medications in patients. and the studies they used for their models had different people with different definitions/inclusion and exclusion criteria.

-- the 3 base studies they used involved single agents: there are no studies actually trying different combinations of meds in randomized controlled trials to see which seem to be the best (ie, we really do need actual studies...)

-- and some of these combinations may be much more synergistic than others. perhaps some are not helpful and potentially detrimental??

so, a thought-provoking mathematical analysis suggesting that there may well be similar approaches to treating those with HFpEF as HFrEF: the likely significant clinical benefits from combinations of medications in those with HFpEF. If confirmed in actual clinical trials (eg RCTs), this is a huge step forward for such a large population of people with heart failure...

geoff

 

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